Kras inhibitor compounds

Abstract

The application provides a KRAS inhibitor compound and application thereof. Specifically disclosed are a heterocyclic compound as shown in formula (I-1) or formula (I-2), a pharmaceutically acceptable salt of the heterocyclic compound, a stereoisomer of the heterocyclic compound, a deuterated derivative of the heterocyclic compound or a solvate of the heterocyclic compound. The compound of the application is novel in structure, and has good activity and selectivity.

Description

[0001] This application claims the following priority:

[0002] Application number: CN202210900237X, application date: 2022-07-28;

[0003] Application number: CN2022111939164, application date: 2022-09-28;

[0004] Application number: CN2023100049248, application date: 2023-01-03;

[0005] Application number: CN2023104033982, application date: 2023-04-14;

[0006] Application number: CN2023105900621, application date: 2023-05-23. Technical Field

[0007] This invention relates to the pharmaceutical field, and more specifically, to a KRAS inhibitor compound and its applications. Background Technology

[0008] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), with 85% of RAS-driven cancers caused by mutations in the KRAS subtype. KRAS mutations are common in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutant tumors, 80% of oncogenic mutations occur at codon 12, with the most common mutations including p.G12D (41%), p.G12V (28%), and p.G12C (14%).

[0009] The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog. KRAS plays a pivotal role in the signal regulation of cell growth. Upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4, upon receiving external signals, transmit these signals downstream via the KRAS protein. When unactivated, the KRAS protein is tightly bound to GDP (guanine diphosphate). Upon activation by guanine nucleotide exchange factors such as SOS1, it binds to GTP (guanine triphosphate), becoming a kinase-active state. Mutations in the KRAS gene can lead to uncontrolled cell growth and tumor progression, independently transmitting growth and proliferation signals downstream, regardless of upstream growth factor receptor signals. Furthermore, the presence or absence of KRAS gene mutations is an important indicator of tumor prognosis. Statistical results show that KRAS G12D is also a common submutation among KRAS subtypes, accounting for 12% in colorectal cancer, 36% in pancreatic cancer, and 4% in non-small cell lung cancer. Therefore, it is very necessary to develop a new KRAS inhibitor, which has great potential to become a new treatment in the field of cancer treatment. Thus, it is necessary to develop more effective, safer, and better pharmacokinetic KRAS inhibitors to meet clinical needs. Summary of the Invention

[0010] This invention provides a KRAS inhibitor compound and its application. Specifically, it discloses heterocyclic compounds as shown in Formula I-1 or Formula I-2, their pharmaceutically acceptable salts, their stereoisomers, deuterated derivatives, or their solvates. The compounds of this invention have novel structures and exhibit good activity and selectivity.

[0011]

[0012] In formulas I-1 and I-2, Cy1 represents a 6-membered aryl or a 6-membered heteroaryl; further, Cy1 may also be arbitrarily replaced by 0-3 elements selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NRa R b -NR a C(O)R a -NR a R b The substituents are replaced;

[0013] In Formula I-1, Cy2 represents a 6-membered aryl or a 6-membered heteroaryl; further, Cy2 may also be arbitrarily replaced by 0-3 radicals selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halogenated (C1-C6), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced;

[0014] Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;X 3 For N or CR X3 ;

[0015] Among them, R X1 R X2 R X3 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NRa C(O)R a -NR a R b ;

[0016] Wherein, L1 and L2 independently represent the absence of, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-, and -NR. a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O),-NR a C(O)(C1-C6 alkylene)-、-(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0017] Among them, R 1 R 2 Each independently represents a 5-16 member saturated or unsaturated cycloalkyl group or a 5-16 member saturated or unsaturated heterocycloalkyl group, and the R... 1 R 2 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a-OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced;

[0018] Among them, Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be affected by O, NH, -C(O), -OC(O)-, -C(O)O-, and -CONR. a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a -replaced;

[0019] Or, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings;

[0020] Among them, R a R b Each can independently represent hydrogen, C1-C6 alkyl, halogenated (C1-C6 alkyl), or C3-C6 cycloalkyl; or R a R b Together with the atoms attached to it, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0021] In addition, the present invention provides a heterocyclic compound as shown in Formula I-1' or Formula I-2', its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative, or solvates thereof:

[0022]

[0023] Among them, in equations I-1' and I-2',

[0024] M 1 Indicates CR M1 Or N; M 2 Indicates CRM2 Or N; M 3 Indicates CR M3 Or N; M 4 Indicates CR M4 Or N; M 5 Indicates CR M5 Or N; M 6 Indicates CR M6 Or N; M 7 Indicates CR M7 Or N; M 8 Indicates CR M8 Or N; M 9 Indicates CR M9 Or N; M 10 Indicates CR M10 Or N;

[0025] Among them, R M1 R M2 R M3 R M4 R M5 R M6 R M7 R M8 R M9 R M10 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced;

[0026] Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;X 3 For N or CR X3 ;

[0027] Among them, R X1 R X2 RX3 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ;

[0028] Wherein, L1 and L2 independently represent the absence of, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-, and -NR. a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O),-NR a C(O)(C1-C6 alkylene)-、-(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0029] Among them, R 1 R 2 Each independently represents a 5-16 member saturated or unsaturated cycloalkyl group or a 5-16 member saturated or unsaturated heterocycloalkyl group, and the R... 1 R 2 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced;

[0030] Among them, Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a -replaced;

[0031] Or, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings;

[0032] Among them, R a R bEach can independently represent hydrogen, C1-C6 alkyl, halogenated (C1-C6 alkyl), or C3-C6 cycloalkyl; or R a R b Together with the atoms attached thereto, they form a 3-6 membered ring, which may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S. In a preferred embodiment of the invention, X... 2 It represents CH or N.

[0033] In a preferred embodiment of the present invention, X 3 Indicates CR X3 Or N, where R X3 Indicates H, halogen, OR a CN, NO2, SF5, POMe2, NH2, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl).

[0034] In a preferred embodiment of the present invention, L1 represents the absence of, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 heterocyclic alkyl)-(C0-C6 alkylene)-, and -NR. a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0035] In a preferred embodiment of the present invention, L1 represents O-C1-C6 alkylene-.

[0036] In a preferred embodiment of the present invention, L1 represents -O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached to them, they form 3-6 saturated or unsaturated rings.

[0037] In a preferred embodiment of the present invention, R 1 The R indicates a 5-16 member saturated or unsaturated heterocyclic alkyl group. 1 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

[0038] In a preferred embodiment of the present invention, R 1 It has any of the following structures:

[0039]

[0040]

[0041] Furthermore, the R mentioned 1 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2Ra , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

[0042] In a preferred embodiment of the present invention, R 1 express:

[0043]

[0044] Among them, R 1' R 2' R 3' R 4' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ;

[0045] Or R 1' With R 2' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 1' With R 2'Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0046] Or R 3' With R 4' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 3' With R 4' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0047] Or R 5' With R 6' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R5' With R 6' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0048] Or R 7' With R 8' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 7' With R 8' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0049] Or R 9' With R 10'Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 9' With R 10' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0050] Or R 11' With R 12' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 11' With R 12' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0051] Or R2' With R 3' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0052] Or R 4' R 5' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0053] Or R 8' R 9'Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0054] Or R 10' R 11' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O.

[0055] In a preferred embodiment of the present invention, R 1' R 2' R 3' R 4' R 5' R 6' R 7' R8' R 9' R 10' R 11' R 12' Each can be independently represented as hydrogen, halogen, hydroxyl, carbonyl, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C2-C6 alkenyl, or C2-C6 alkynyl.

[0056] In a preferred embodiment of the present invention, wherein the R 1 It has the following structure:

[0057]

[0058] Among them, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' It has any of the above definitions.

[0059] In a preferred embodiment of the present invention, wherein the R 1 It has the following structure:

[0060]

[0061] Wherein, ring A is a 3-6 membered ring, and ring A may be arbitrarily replaced by 0-2 elements selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced;

[0062] Among them, R 1' R 4' R 5' R 6' R 7' R8' R 9' R 10' R 11' R 12' It has any of the above definitions.

[0063] In a preferred embodiment of the present invention, wherein the R 1 It has the following structure:

[0064]

[0065] Among them, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' It has any of the above definitions, where R L R L’ Each can independently represent hydrogen, C1-C6 alkyl, or halogen.

[0066] In a preferred embodiment of the present invention, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' Each of these can be independently represented as hydrogen, halogen, hydroxyl, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), or hydroxyl (C1-C6 alkyl); R 3' R 4' Together with the atoms respectively bonded thereto, they form a 3-6 membered ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may arbitrarily contain 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a-C(O)NR a R b -NR a C(O)R a Substituents:

[0067]

[0068] In a preferred embodiment of the present invention, L2 represents the absence of, -O-C1-C6 alkylene-, -C1-C6 alkylene-, -C1-C6 alkylene-O-, and -NR. a -C1-C6 alkylene-, -C1-C6 alkylene-NR a -

[0069] In the preferred embodiment of the present invention, L2 represents non-existence.

[0070] In a preferred embodiment of the present invention, R 2 It is any one of the following ring structures: (i), (ii), or (iii)

[0071]

[0072] Among them, W 1 Represents -(CR) W1 R W2 ) p -、-(CR W1 R W2 ) p -O-、-O-(CR W1 R W2 ) p -、-NR a -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -NR a -, -CH = CH- or NR W1 ;

[0073] Among them, R W1 R W2 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a-C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b Or R W1 R W2 Together with the carbon atom attached thereto, they form a 3-8 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; and the ring may also arbitrarily be separated by 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0074] Among them, R 1 "、R 2 "、R 3 "、R 4 "、R 5 "、R 6 "、R 7 "、R 8 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NRa R b -NR a C(O)R a -NR a R b ;

[0075] Or R 1 "with R" 2 "Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR." a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0076] Or R 3 "with R" 4 "Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR." a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0077] Or R 5 "with R" 6 "Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR." a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0078] Or R 7 "with R" 8 "Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR." a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0079] Or R 2 "with R" 3"Together with the atoms respectively attached, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR." a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0080] Or R 4 "with R" 5 "Together with the atoms respectively attached thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0081] Or R 6 "with R" 7"Together with the atoms respectively attached thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 member heterocyclic alkyl, 3-6 member heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O;

[0082] Or R 5 "with R" W1 Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O.

[0083] In a preferred embodiment of the present invention, R 2 It can be any of the following ring structures:

[0084]

[0085] Furthermore, the R mentioned 2It can be arbitrarily composed of 0-4 ions selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(0)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

[0086] In a preferred embodiment of the present invention, R 2 It can be any of the following ring structures:

[0087]

[0088] Furthermore, the R mentioned 2 It can be arbitrarily composed of 0-4 ions selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(0)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

[0089] In a preferred embodiment of the present invention, R 2 It can be any of the following ring structures:

[0090]

[0091] In a preferred embodiment of the present invention, M 1 To M 10 It represents CH or N.

[0092] In a preferred embodiment of the present invention, M 1 To M 10 It represents CH.

[0093] In a preferred embodiment of the present invention, wherein,

[0094] Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be substituted by O, NH, -C(O), -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -P(O)R a - Replaced.

[0095] In a preferred embodiment of the present invention, Y 1 Y 2 Together they form -(C1-C 10 (alkylene)-NR a -、-O-(C1-C 10 (alkylene)-NR a -、-NR a (C1-C 10 alkylene)-O-, -(C1-C 10 alkylene)-O-, -(C1-C 10 alkylene)-C(O)NR a -、-(C1-C 10 (alkylene)-NR a C(O)-、-(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-O-, -(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 (alkylene)-NR a -(C1-C 10 alkylene)-, -(C1-C 10 (alkylene)-NR a -(C1-C 10 alkylene)-O-, -(C1-C 10 alkylene)-O-(C1-C 10 (alkylene)-NR a -、-NRa -(C1-C 10 alkylene)-, -O-(C1-C 10 alkylene)-,-C(O)NR a -(C1-C 10 alkylene)-, -NR a C(O)-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -O-(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-C(O), -(C1-C 10 alkylene)-C(O)-, -O-(C1-C 10 alkylene)-C(O)-, -C(O)-(C1-C 10 alkylene)-, -C(O)-(C1-C 10 alkylene)-O-, -O-(C1-C 10 alkylene)-C(O)NR a -、-C(O)NR a -(C1-C 10 alkylene)-O-, -(C1-C 10 alkylene)-S-, -S-(C1-C 10 Alkylene)-.

[0096] In a preferred embodiment of the present invention, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings.

[0097] In a preferred embodiment of the present invention, Y 1 Y 2 Together they form any of the following structures:

[0098]

[0099] In a preferred embodiment of the present invention, the following structure is provided:

[0100]

[0101]

[0102] Terminology Definition

[0103] It is particularly noteworthy that, in this document, when referring to a "compound" having a specific structural formula, the term generally also encompasses its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives, as well as its alternative forms such as pharmaceutically acceptable salts, solvates, and hydrates. It is well known to those skilled in the art that salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that, when referring to a compound in this document, its pharmaceutically acceptable salts are generally also included, and consequently, its solvates and hydrates.

[0104] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included.

[0105] The pharmaceutically acceptable salts described in this invention can be formed using inorganic or organic acids. A "pharmaceutically acceptable salt" is defined as a salt that, within a reasonable medical judgment, is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, a free base can react with a suitable acid. Furthermore, when the compounds of this invention contain an acidic moiety, suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts (e.g., sodium or potassium salts) and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharmaceutically usable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and ammonium cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0106] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0107] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0108] The term "solvent" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0109] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration exhibit different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon atoms or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations in cyclohexane. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention can have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. Compounds of this invention can exist as tautomers, having different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of formula (I) are included within the scope of this invention.

[0110] The "isotope derivative" of this invention refers to the molecule in which the compound is isotopically labeled. Commonly used isotopes for isotopic labeling are: hydrogen isotopes: 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium. 2 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby reducing the dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0111] The compounds or pharmaceutical compositions of the present invention can be formulated into dosage forms for oral or parenteral administration (including intramuscular, intravenous, and subcutaneous routes, and intratumoral injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0112] The pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with, for example, a carrier including cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, and diluent. Examples of carriers used in the injectable compositions of the present invention are water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol ester, surfactant, suspending agent, and emulsifier.

[0113] Other features of the invention will become apparent as the exemplary embodiments are described. The embodiments are given to illustrate the invention and are not intended to be limiting. The following examples use the methods disclosed in the invention to prepare, separate, and characterize.

[0114] Unless otherwise specified, the terms used in this application (including the specification and claims) are defined as follows. It should be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0115] In the specification and claims, the given chemical formula or name shall cover all stereo and optical isomers and racemic products containing such isomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are covered within this invention. This invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of this invention, which can be separated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be separated in optically active or racemic forms. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. In the preparation of enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the method conditions, the end products of this invention are obtained in free (neutral) or salt form. Both the free form and salts of these end products are within the scope of this invention. If necessary, one form of the compound can be converted into another. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms, and salts can exist in a variety of tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within the scope of this invention.

[0116] Unless otherwise defined, the definitions of substituents in this invention are independent and not related to each other. For example, for R in a substituent... a (or R) b For R, the definitions of different substituents are independent. Specifically, for R a (or R) b Choosing a definition for a substituent does not mean that R a (or R) b The same definition applies to all other substituents. More specifically, for example (a non-exhaustive list only) for NR... a Rb In the middle, when R a (or R) b When the definition of ) is taken from hydrogen, it does not mean that in -C(O)-NR a R b In the middle, R a (or R) b It must be hydrogen.

[0117] Unless otherwise defined, when a substituent is labeled “optionally substituted,” the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamide (e.g., -SO2NH2), substituted sulfonamide, nitro, cyano, carboxyl, carbamoyl (e.g., -CONH2), substituted carbamoyl (e.g., -CONHalkyl), -CONHaryl, -CONHarylalkyl, or having two substituents selected from alkyl, aryl, or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0118] As used herein, the terms “alkyl” or “alkylene” are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, “C1-C6 alkyl” means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl.

[0119] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.

[0120] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 1-butynyl.

[0121] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" indicates an alkyl group as defined above that has a specified number of carbon atoms and is linked by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0122] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0123] The term "aryl," alone or as part of a larger group such as "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc. Fused aryl groups can be attached to another group at a suitable position on a cycloalkyl ring or an aromatic ring. Example: Dashed lines drawn from a ring system indicate that the bond can be attached to any suitable ring atom.

[0124] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl groups refer to C3-C8 cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include cycloalkyl groups with bridged rings, spiro rings, or fused rings.

[0125] The term "heterocyclic alkyl" refers to a cycloalkyl structure in which at least one carbon atom in the ring is replaced by a heteroatom selected from O, N, S, or Se.

[0126] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Branched cyclic alkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl." Bicyclic cyclic alkenyl groups include cyclic alkenyl groups with bridged rings, spirorings, or fused rings.

[0127] "Halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0128] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, which is oxygen-bridged and has a specified number of carbon atoms. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above, which is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0129] In this disclosure, when referring to substituent groups, the expression Cx1-Cx2 is used, which indicates that the number of carbon atoms in the substituent group can be from x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0130] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0131] In this invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0132] The term "heteroaryl" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycle that is fully unsaturated or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups, wherein any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted at a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1.

[0133] The reagents and raw materials used in this invention are all commercially available.

[0134] The positive and progressive effects of this invention are as follows: the compounds of this invention exhibit good cell proliferation inhibitory activity against the KRAS G12D-mutant gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. They also demonstrate good stability in liver microsomes, hepatocytes, plasma, and whole blood, good PK properties, and significant tumor-suppressing effects. Detailed Implementation

[0135] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0136] The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvent used for the measurements is noted in the spectral analysis.

[0137] MS measurements were performed using Agilent 1200-G1956A / 1200-6110A / 1200-6140A / 1260-6125B / Prime-6125B / 1260-6120 LC-MS / MS systems, SHIMADZU 20A-2010 / 20A-2020 LC-MS / MS systems, and Waters ACQ-QDA LC-MS / MS systems.

[0138] HPLC analysis was performed using a SHIMADZU 20A high-performance liquid chromatograph.

[0139] SFC analysis was performed using a Waters UPCC with PDA Detector and QDa Detector ultra-high performance phase chromatography system. 2 Ultra-high performance liquid chromatograph with PDA detector, Agilent 1260 high performance liquid chromatograph with DAD detector, Shimadzu LC-20AB high performance liquid chromatograph with PDA detector, Shimadzu LC-20AD high performance liquid chromatograph with PDA detector.

[0140] Preparative HPLC separation was performed using a Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322pump, and Gilson 156 UV Detector.

[0141] SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, and Prep350 SFC SYSTEM.

[0142] Rapid column chromatography separation was performed using the Biotage IsoleraOne rapid preparative chromatograph.

[0143] The silica gel plates used for thin-layer chromatography are GF254 acrylic adhesive silica gel plates from Anhui Liangchen Silicon Source Materials Co., Ltd. The silica gel plates used in thin-layer chromatography (TLC) are 0.25 mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.5 mm in diameter.

[0144] Pressurized hydrogenation reaction hydrogenation bottle and hydrogen cylinder.

[0145] The microwave reaction was performed using a Biotage Initiator+ microwave synthesizer.

[0146] The glove box uses a custom-made DELLIX glove box.

[0147] Intermediate 1: tert-butyl(1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0148]

[0149] Step 1: A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.50 g, 14.96 mmol) and urea (8.98 g, 149.56 mmol) was stirred at 200 °C for 2 hours. After cooling to 100 °C, water (30 mL) was added, and the mixture was stirred for 1 hour. The mixture was filtered, and water (25 mL) was added to the solid product. The mixture was stirred at 50 °C for 1 hour, filtered, and water (25 mL) was added to the solid product. The mixture was stirred at 25 °C for 12 hours, filtered, and the solid was dried under vacuum to obtain the crude compound 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g), which was a gray solid. LCMS (ESI): [M+H] + =258.8.

[0150] Step 2: At 0°C, potassium nitrate (3.43 g, 33.97 mmol) was added to a concentrated sulfuric acid solution (35 mL) of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g, 14.96 mmol). The solution was stirred at 0°C for 1 hour. The mixture was poured into water (35 mL), the solid was filtered off, and dried under vacuum to give a gray solid compound 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (3.50 g, 11.51 mol, yield 77%). LCMS (ESI): [M+H] + =303.9. 1 H NMR (400MHz, DMSO-d6) δppm 11.98 (br s, 1H), 11.85 (s, 1H), 8.34 (s, 1H).

[0151] Step 3: At 0°C, diisopropylethylamine (2.45 mL, 14.80 mmol) was added to a solution of 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (1.50 g, 4.93 mmol) and phosphorus oxychloride (3.67 mL, 39.47 mmol) in toluene (22 mL). The mixture was stirred at 100°C for 3 hours under nitrogen protection. The mixture was evaporated to dryness, ethyl acetate (30 mL) was added, followed by ice and ice water (30 mL), and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g), which was a gray solid. LCMS (ESI): [M + H] + =341.8.

[0152] Step 4: Triethylamine (1.84 mL, 13.20 mmol) was added to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g, 4.55 mmol) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (965 mg, 4.55 mmol) in dichloromethane (15 mL x 3). The mixture was stirred at 25 °C for 2 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give the gray solid compound (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol, yield 25%). LCMS (ESI): [M+H] + =517.7.

[0153] Step 5: Diisopropylethylamine (944 μL, 5.71 mmol) was added to a trifluoroethanol (4.4 mL) solution of (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol). The mixture was stirred at 70 °C for 12 hours and then evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a yellow solid compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (500 mg, 0.86 mmol, 75% yield). LCMS(ESI):[M+H] + =581.7.

[0154] Step 6: Add ammonium chloride (1.84 g, 34.46 mmol) and iron powder (0.96 g, 17.23 mmol) to a solution of tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (2.00 g, 3.45 mmol) in ethanol (40 mL) and water (20 mL). Stir the mixture at 80 °C for 2 hours under nitrogen protection, filter, and wash the solid with dichloromethane (60 mL). The filtrate was added to water (100 mL) and extracted with dichloromethane (100 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude compound tert-butyl(1R,5S)-3-(6-amino-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.95 g), which was a brown solid. LCMS (ESI): [M + H] + =551.9.

[0155] Step 7: Under nitrogen protection, tert-butyl(1R,5S)-3-(6-amino-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.93 g, 3.51 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) In a 40 mL solution of 1,4-dioxane (2.34 g, 4.56 mmol) of heterocyclopentan-2-ylnaphth-1-ylethynyltriisopropylsilane, potassium phosphate (1.5 M, 7.0 mL, 10.52 mmol) and methanesulfonyloxy(dadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (255.4 mg, 0.35 mmol) were added. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. Dilute with water (20 mL), extract with ethyl acetate (20 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and purify the residue by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a brown solid compound tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.40 g, 1.64 mmol, yield 47%). LCMS (ESI): [M+H] + =856.5.

[0156] Step 8: Add cesium fluoride (2431.1 mg, 16.00 mmol) to a solution of tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1370.0 mg, 1.60 mmol) in N,N-dimethylformamide (27 mL). Stir the mixture at 25 °C for 1 hour under nitrogen protection. Dilute with water (90 mL), extract with ethyl acetate (90 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a brown solid compound, tert-butyl(1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (720.0 mg, 1.03 mmol, yield 64%). LCMS (ESI): [M+H] + =700.2.

[0157] Intermediate 2: Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester

[0158]

[0159] Step 1: 2-Amino-4-bromo-3-fluorobenzoic acid (25.0 g, 106.83 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-iodosuccinimide (36.0 g, 160.24 mmol) was added. The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water (3 L), slurried at room temperature for 1 hour, filtered, and the filter cake was washed with water (300 mL * 3). The filter cake was concentrated to give the yellow compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94.47 mmol, yield 88%). LCMS (ESI): [M+H] + =359.9.

[0160] Step 2: Compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.35 mmol) and urea (50.0 g, 833.52 mmol) were added to a reaction flask. The reaction system was heated to 200 °C and reacted for 4 hours. After cooling to room temperature, water (300 mL) was added for dilution, and the mixture was heated to 80 °C and stirred for half an hour. The mixture was filtered while hot, and the filter cake was subjected to the same stirring and filtration process twice. The filter cake was concentrated under reduced pressure to obtain the yellow compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (26.7 g, 69.36 mmol, yield 83%). LCMS (ESI): [M+H] + =387.0.

[0161] Step 3: 7-Bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7 g, 64.17 mmol) was added to phosphorus oxychloride (300 mL), and diisopropylethylamine (40.0 mL, 224.59 mmol) was added at 0 °C. The mixture was stirred at 130 °C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was added to ice water (500 mL), and extracted with dichloromethane (500 mL * 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-4% gradient of methanol / dichloromethane) to give 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (26.7 g, 62.88 mmol, yield 98%). LCMS (ESI): [M+H] + =420.8.

[0162] Step 4: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0 g, 23.71 mmol) in dichloromethane (100 mL), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.54 g, 26.08 mmol) and triethylamine (10.0 mL, 71.12 mmol) were added, and the reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-36% gradient of ethyl acetate / petroleum ether) to give tert-butyl(1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (3.60 g, 5.93 mmol, yield 25%). LCMS(ESI):[M+H] + =597.0.

[0163] Step 5: Add diisopropylethylamine (37.7 mL, 212.51 mmol) to a 2,2,2-trifluoroethanol (193 mL) solution of tert-butyl(1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (25.4 g, 42.50 mmol), and stir the reaction solution at 70 °C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl(1S,5R)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20.1 g, 30.6 mmol, yield 72%). LCMS (ESI): [M+H] + =661.3.

[0164] Step 6: At 25°C, tert-butyl(1S,5R)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.00 g, 1.51 mmol) was dissolved in dioxane (20.0 mL), and tributyl(1-ethoxyvinyl)stanane (510 mg, 1.41 mmol) was added. Tetra(triphenylphosphine)palladium (170 mg, 0.15 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a white solid compound tert-butyl(1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (680 mg, 1.12 mmol, yield 74%). LCMS (ESI): [M+H] + =605.0.

[0165] Step 7: At 25°C, tert-butyl(1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (400 mg, 0.66 mmol) and hydrochloric acid (2 M aqueous solution, 1.65 mL, 3.30 mmol) were added to tetrahydrofuran (8.00 mL), and the reaction system was reacted at 20°C for 2 hours. The pH was adjusted to 7 by adding saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (4 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to give a white solid compound tert-butyl(1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (220 mg, 0.38 mmol, yield 58%). LCMS (ESI): [M+H] + =577.2.

[0166] Step 8: 2.00 g (3.46 mmol) of tert-butyl(1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in dioxane (20 mL) and sodium hydroxide (1.5 M aqueous solution, 18.5 mL, 27.7 mmol). Liquid bromine (0.53 mL, 10.4 mmol) was slowly added dropwise at 0 °C. The reaction was stirred at 0 °C for 3 hours, and then stirred at 20 °C for 16 hours. Add water (50 mL) to the reaction solution, adjust the pH to 4 with 2M dilute hydrochloric acid, extract with ethyl acetate (50 mL * 3), wash the organic phase with saturated brine (50 mL), dry with sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by rapid column chromatography (silica gel, 0-40% gradient ethyl acetate / petroleum ether) to give 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (1.00 g, 1.73 mmol, yield 50%). LCMS (ESI): [M + H + =581.3.

[0167] Step 9: Add 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (350 mg, 0.60 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)naphth-1-yl) 402 mg (0.78 mmol) of triisopropylsilane (ethynyl) and 1.20 mL (1.81 mmol) of potassium phosphate (1.5 M aqueous solution, 1.81 mmol) were dissolved in dioxane (3.50 mL). Methanesulfonyloxy(dadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (44 mg, 0.06 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. Four identical batches of the same reaction were combined, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to give compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol, yield 30%). LCMS (ESI): [M+H] + =885.3.

[0168] Step 10: At 0°C, add iodomethane (224 mg, 1.58 mmol) to a dimethylformamide (7 mL) suspension of compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (650 mg, 0.72 mmol) and potassium carbonate (329 mg, 2.38 mmol). Stir the reaction mixture at 20°C for 16 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL * 2), the organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (600 mg), which was a yellow oily liquid. LCMS (ESI): [M + H] + =899.3.

[0169] Step 11: Add cesium fluoride (1.00 g, 6.60 mmol) to a dimethylformamide (6 mL) solution of methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (600 mg, 0.66 mmol) and stir at 20 °C for 3 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phase was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to give methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester (400 mg, 0.53 mmol, yield 80%). LCMS (ESI): [M+H] + =743.6.

[0170] Intermediate 3: (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolino

[0171]

[0172] Step 1: At -40°C, (R)-3-methylpiperidin-3-ol hydrochloride (2.49 g, 16.43 mmol) and diisopropylethylamine (25.0 mL, 140.8 mmol) were added to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (8.00 g, 23.47 mmol) in dichloromethane (50 mL x 3). The solution was stirred at -40°C for 4 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to give a yellow solid (R)-1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (7.50 g, 17.87 mmol, yield 76%). LCMS (ESI): [M+H] + =420.9.

[0173] Step 2: At 20°C, diisopropylethylamine (12.5 mL, 71.49 mmol) was added to a trifluoroethanol (80 mL) solution of (R)-1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (7.50 g, 17.87 mmol). The solution was stirred at 70°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid compound (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (6.80 g, 14.07 mmol, yield 78%). LCMS (ESI): [M+H] + =483.0.

[0174] Step 3: At 25°C and under a nitrogen atmosphere, add methanesulfonyloxy(dadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (18.39 g, 25.25 mmol) to a solution of (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (61 g, 126.24 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronic-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (67.94 g, 132.55 mmol), cesium carbonate (123.39 g, 378.71 mmol) in toluene (1000 mL) and water (250 mL). The solution was stirred at 100 °C for 16 hours. The solution was concentrated and purified, and purified by rapid column chromatography (silica gel, 0-20% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound (3R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (90.00 g, 107.24 mmol, yield 85%). LCMS (ESI): [M+H] + =789.5.

[0175] Step 4: At 25°C, cesium fluoride (61.62 g, 405.64 mmol) was added to a solution of (3R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (64.00 g, 81.13 mmol) in dimethylformamide (500 mL), and the reaction was stirred at 25°C for 2 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid column chromatography (silica gel, 0-30% gradient tetrahydrofuran / petroleum ether) to give a yellow solid compound (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (35.00 g, 55.33 mmol, yield 68%). LCMS (ESI): [M+H] + =633.1.

[0176] Step 5: Under a nitrogen atmosphere at 25°C, cuprous iodide (1.05 g, 5.53 mmol) and tetrakis(triphenylphosphine)palladium (12.79 g, 11.07 mmol) were added to a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (35.00 g, 55.33 mmol) and (2E)-3-iodoacrylate (17.60 g, 83.00 mmol) in triethylamine (175 mL) and dimethylformamide (260 mL). The reaction was stirred at 50°C for 2 hours. The reaction mixture was filtered, the filtrate was evaporated to dryness, and the crude product was purified by rapid column chromatography (silica gel, 0-35% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound (E)-5-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)pent-2-en-4-acetylic acid methyl ester (40.00 g, 47.45 mmol, yield 86%). LCMS (ESI): [M+H] + =717.0.

[0177] Step 6: At 25°C, platinum dioxide (2.70 g, 11.89 mmol) was added to a methanol (1500 mL) solution of methyl (E)-5-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)pent-2-ene-4-ynyl acetic acid (27.00 g, 37.68 mmol). The mixture was stirred at 25°C for 16 hours under a hydrogen atmosphere at 15 psi. The solution was filtered, the filtrate was concentrated, and the crude product was purified by rapid column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / dichloromethane) to give a red solid compound, methyl 5-(8-(6-amino-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)valerate (16.00 g, 23.01 mmol, yield 61%). LCMS (ESI): [M+H + =693.2.

[0178] Step 7: Lithium hydroxide (3.09 g, 73.63 mmol) was added to a solution of methyl 5-(8-(6-amino-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)valerate (17.00 g, 24.54 mmol) in tetrahydrofuran (170 mL) and water (34 mL) at 25 °C. The reaction solution was stirred at 50 °C for 16 hours. The reaction solution was diluted with water (200 mL), the pH was adjusted to 4 with concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL * 3). The combined organic layers were dried, filtered, and the filtrate was concentrated to give a brown solid compound, 5-(8-(6-amino-8-fluoro-4-((S)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)valeric acid (17.00 g, 22.54 mmol, yield 92%). LCMS (ESI): [M+H + =679.3.

[0179] Step 8: At 25°C, tri-n-butyl cyclic phosphoric anhydride (40.91 g, 75.15 mmol) was added to a solution of 5-(8-(6-amino-8-fluoro-4-((S)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)valeric acid (17.00 g, 25.05 mmol) and diisopropylethylamine (175 mL, 1002.01 mmol) in dioxane (660 mL), and the mixture was stirred at 60°C for 16 hours. The reaction was quenched with water (600 mL), extracted with ethyl acetate (600 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid column chromatography (silica gel, 0-50% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (13.00 g, 19.68 mmol, yield 79%). LCMS (ESI): [M+H + =661.3.

[0180] Step 9: At 0°C, add tert-butyldifluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (2.0 g, 3.03 mmol) in portions to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (2.0 g, 3.03 mmol) in dichloromethane (20 mL). Stir the mixture in portions at 20°C for 3 hours under nitrogen protection. Add water (20 mL), extract with dichloromethane (20 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Purify the residue by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether / dichloromethane, v / v)) to give a yellow solid (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.92 g, 2.48 mmol, 82% yield). LCMS (ESI): [M+H] + =775.3.

[0181] Step 10: Add benzylsilane (1.91 mL, 15.49 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (600.0 mg, 0.77 mmol) and (1,5-cyclooctadiene)iridium(I) chloride dimer (52.0 mg, 0.08 mmol) in tetrahydrofuran (48 mL). Stir the mixture at 25 °C for 12 hours under nitrogen protection and evaporate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether / dichloromethane, v / v)) to give a yellow solid (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (430 mg, 0.57 mmol, yield 73%). LCMS (ESI): [M+H + =761.3.

[0182] Intermediate 4: (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolino

[0183]

[0184] Step 1: Add triethylamine (1.03 mL, 7.40 mmol) to a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (3.9 g, 6.17 mmol), 4-methylbenzenesulfonyl azide (1.95 g, 7.40 mmol), and cuprous iodide (0.12 g, 0.62 mmol) in chloroform (50 mL) and water (0.28 mL, 15.41 mmol). The mixture was stirred for 12 hours under nitrogen protection and at 20°C. It was then diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-p-methylbenzenesulfonylacetamide (5.0 g), which was a brown solid. LCMS (ESI): [M+H] + =820.0.

[0185] Step 2: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-p-methylbenzenesulfonylacetamide (5.4 g, 6.59 mmol) in N,N-dimethylformamide (50 mL), iodomethane (1.23 mL, 19.76 mmol) and potassium carbonate (2.73 g, 19.76 mmol) were added. The mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthyl-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (2.38 g, 2.85 mmol, yield 43%). LCMS (ESI): [M+H] + =834.2.

[0186] Step 3: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (11.5 g, 13.79 mmol) and triethylamine (9.59 mL, 68.96 mmol) in dichloromethane (140 mL), tert-butyldimethylsilyltrifluoromethanesulfonate (5.20 mL, 41.38 mmol) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 16 hours. It was diluted with water (40 mL), extracted with dichloromethane (40 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give a brown solid compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (12.7 g, 13.41 mmol, yield 97%). LCMS (ESI): [M+H] + =948.4.

[0187] Step 4: At -70°C, add 1M diisobutylaluminum hydride (42.19 mL, 42.19 mmol) to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (12.50 g, 13.19 mmol) in 155 mL of dichloromethane. Stir the mixture at -70°C for 1 hour, quench with acetic acid (7.25 mL, 126.58 mmol), dilute with water (100 mL), stir, and let stand for 16 hours. Extraction was then performed using dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether:dichloromethane = 3:1)) to give compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)acetaldehyde (7.70 g, 10.08 mmol, yield 76%), as a brown solid. LCMS (ESI): [M+H] + =765.3.

[0188] Step 5: At 0°C, borane / tetrahydrofuran (1M, 41mL, 40.71mmol) was added to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)acetaldehyde (18.50g, 24.19mmol) in 190mL of tetrahydrofuran. The reaction mixture was stirred at 10°C for 16 hours. The reaction mixture was quenched with methanol at 0°C. The mixture was concentrated under reduced pressure to give a brown solid compound, 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethanol (18.50 g, 21.71 mmol, 90% yield). LCMS (ESI): [M+H] + =767.8.

[0189] Step 6: Under nitrogen protection, ethyl diazonium chloride (0.62 mL, 5.87 mmol) was added dropwise to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethanol (1.0 g, 1.30 mmol) and rhodium acetate dimer (57.6 mg, 0.13 mmol) in dichloromethane (10.0 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was quenched with methanol (5 mL) and evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether: dichloromethane = 10:1)) to give a brown oily crude compound, ethyl acetate 2-(2-(8-(4-(((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy)ethyl acetate (1.20 g). LCMS (ESI): [M+H] + =853.3.

[0190] Step 7: Add wet palladium on carbon (200.0 mg) to a solution of ethyl acetate (1.0 g, 0.28 mmol) in 40 mL. The mixture was stirred at 20°C for 12 hours under hydrogen (45 psi), filtered, and the filtrate was concentrated under reduced pressure to give 1.0 g of ethyl acetate (2-2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy). LCMS (ESI): [M+H] + =823.3.

[0191] Step 8: Add lithium hydroxide (153.0 mg, 3.65 mmol) to a solution of 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy)ethyl acetate (1.0 g, 1.22 mmol) in tetrahydrofuran (8.0 mL) and water (2.0 mL). Stir the mixture at 50 °C for 3 hours, then at 25 °C for 12 hours, and adjust the pH to 5-6 using 1 M hydrochloric acid solution. Extracted with ethyl acetate (5 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a yellow solid compound 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy)acetic acid (0.8 g, 1.01 mmol, yield 83%). LCMS (ESI): [M+H] + =795.3.

[0192] Step 9: Under a nitrogen atmosphere at 25°C, n-butylphosphonic anhydride (50% ethyl acetate solution, 6.78 g, 12.45 mmol) was added to a solution of 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy)acetic acid (3.30 g, 4.15 mmol) and diisopropylethylamine (29 mL, 166.06 mmol) in dioxane (135 mL). The reaction solution was stirred at 60°C for 2 hours. Water (160 mL) and ethyl acetate (160 mL * 3) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (3.04 g, 3.33 mmol, yield 80%). LCMS(ESI):[M+H + =777.5.

[0193] Step 10: Dissolve compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (900 mg, 1.2 mmol) and phenylsilane (2.86 mL, 23.2 mmol) in tetrahydrofuran (70 mL), lower the temperature to 0 °C, add bis(1,5-cyclooctadiene)iridium(I) chloride dimer (78 mg, 0.1 mmol) under nitrogen atmosphere, and stir at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-20% gradient tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give a yellow solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.7 mmol, yield 56%). LCMS (ESI): [M+H] + =763.3.

[0194] Step 11: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL), add iodomethane (81.0 μL, 1.32 mmol) and cesium carbonate (235 mg, 0.72 mmol). Stir the mixture at 25 °C for 16 hours. Dilute with water (3 mL), extract with ethyl acetate (5 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (petroleum ether / dichloromethane, v / v)) to give a yellow solid (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol, 90% yield). LCMS (ESI): [M+H] + =777.3.

[0195] Intermediate 5: tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0196]

[0197] Step 1: Under nitrogen atmosphere, tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (3.10 g, 5.34 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborane) In a mixed solution of cyclopentan-2-yl)naphthyl)ethynyl)triisopropylsilane (3.56 g, 6.94 mmol) in toluene (124 mL) and water (31.0 mL), cesium carbonate (5.22 g, 16.03 mmol) and methanesulfonyloxy(dadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (0.78 g, 1.07 mmol) were added. The mixture was stirred at 100 °C for 16 hours. The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL * 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound, tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (3.27 g, 3.69 mmol, yield 69%). LCMS (ESI): [M+H] + =886.1.

[0198] Step 2: At 25°C, tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (5.00 g, 5.64 mmol) and cesium fluoride (4.29 g, 28.22 mmol) were added to N,N-dimethylformamide (50.0 mL), and the reaction system was reacted at 20°C for 16 hours. The solution was diluted with water (30 mL), extracted with ethyl acetate (15 mL * 3), and the combined organic phases were dried over anhydrous magnesium sulfate. After filtration, the filtrate and residue were purified by rapid column chromatography (silica gel, 0-20% gradient tetrahydrofuran / petroleum ether) to give a white solid compound tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.50 g, 2.03 mmol, yield 36%). LCMS (ESI): [M+H] + =730.0.

[0199] Step 3: At 25°C, tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (300 mg, 0.41 mmol) and ethyl diazonium (56.3 mg, 0.49 mmol) were dissolved in acetonitrile (6.00 mL), and cuprous iodide (7.83 mg, 0.04 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown oily compound tert-butyl(1R,5S)-3-(7-(8-(4-ethoxy-4-oxobut-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (65% purity, 310 mg, 0.24 mmol, yield 60%). LCMS (ESI): [M+H] + =816.3.

[0200] Step 4: At 25°C, tert-butyl(1R,5S)-3-(7-(8-(4-ethoxy-4-oxobut-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (65% purity, 280 mg, 0.22 mmol) was dissolved in ethyl acetate (10.0 mL), and dry palladium on carbon (200 mg) was added. The reaction system was carried out at 20°C for 16 hours under a hydrogen atmosphere of 15 psi. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a brown oily compound, tert-butyl(1R,5S)-3-(6-amino-7-(8-(4-ethoxy-4-oxobutyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (65% purity, 241 mg, 0.20 mmol, yield 89%). LCMS (ESI): [M+H] + =790.5.

[0201] Step 5: At 25°C, tert-butyl(1R,5S)-3-(6-amino-7-(8-(4-ethoxy-4-oxobutyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (65% purity, 230 mg, 0.20 mmol) and lithium hydroxide (73.3 mg, 1.74 mmol) were added to a mixed solvent of tetrahydrofuran (4.60 mL) and water (920 μL). The reaction system was then reacted at 60°C for 16 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 1N hydrochloric acid. Extraction was performed with ethyl acetate (5 mL * 3). The organic phase was concentrated under reduced pressure to obtain a brown solid compound, 4-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)butyric acid (130 mg, 0.17 mmol, yield 85%). LCMS (ESI): [M+H] + =762.3

[0202] Step 6: At 25°C, add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (150 mg, 0.39 mmol) to a solution of 4-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)butyric acid (130 mg, 0.17 mmol) and N-methylmorpholine (66.3 mg, 0.66 mmol) in 1-methyl-2-pyrrolidone (2.00 mL). The reaction system was reacted at 20°C for 2 hours, and then the temperature was increased to 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (3 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-40% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecanoin[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (80% purity, 160 mg, 0.17 mmol, yield 99%). LCMS (ESI): [M+H] + =744.1

[0203] Intermediate 6: (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0204]

[0205] Step 1: Add hydrogen chloride (4M dioxane solution, 7.86 mL, 31.46 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (200 mg, 0.26 mmol) in acetonitrile (2.00 mL). Stir the solution at 25 °C for 48 hours. The reaction solution was concentrated under vacuum, and the residue was purified by rapid column chromatography (silica gel, 0-15% gradient methanol / dichloromethane) to give a brown solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (157 mg, 0.26 mmol, 99% yield). LCMS (ESI): [M+H] + =605.1. 1 H NMR (400MHz, CD3OD) δppm 8.18-7.94(m,1H),7.77(dd,J=6.1,9.0Hz,1H),7.48-7.25(m,2H),7.07-6.93(m,1H),5.18(br d,J=7.8Hz,2H),3.86(br s,1H),3.70-3.53(m,4H),3.53-3.37(m,3H),3.29-3.10(m,2H),2.79- 2.68(m,1H),2.62-2.47(m,1H),2.07-1.96(m,4H),1.46-1.34(m,3H).

[0206] Step 2: Diisopropylethylamine (123 μL, 0.69 mmol) was added to a solution of compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (140 mg, 0.23 mmol) in dichloromethane (1.4 mL). Trifluoromethanesulfonic anhydride (39.0 μL, 0.23 mmol) was slowly added dropwise at -78 °C, and the solution was stirred at -70 °C for 4 hours. After the reaction was complete, the mixture was quenched with water (1 mL), extracted with dichloromethane (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to give a yellow solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yltrifluoromethanesulfonate (49.0 mg, 0.07 mmol, yield 29%). LCMS (ESI): [M+H] + =737.2.

[0207] Step 3: Under nitrogen protection, compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yltrifluoromethanesulfonate (45.0 mg, 61.09 μmol), palladium acetate (4.11 mg, 18.33 μmol), and triphenylphosphine (9.64 mg, 36.65 μmol) were added to N,N-dimethylformamide (2.25 mL), followed by the addition of triethylamine (25.5 μL, 0.18 mmol) and formic acid (6.91 μL, 0.18 mmol). The solution was stirred at 80 °C for 30 minutes. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (1 mL), and extracted with ethyl acetate (1 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient tetrahydrofuran / dichloromethane) to give a brown solid compound (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (27.0 mg, 45.87 μmol, yield 75%). LCMS (ESI): [M+H] + =589.2. 1 H NMR (400MHz, CDCl3) δppm7.99(d,J=8.3Hz,1H),7.89(dd,J=6.0,8.9Hz,1H),7.52(t,J=7.2Hz,1H),7.39-7.27(m,3H),4.95-4.75(m,2H ),4.36-4.07(m,3H),4.01-3.86(m,1H),3.62-3.30(m,4H),3.19-3.05(m,2H),2.79-2.57(m,2H),2.12-1.67(m,4H),1.38-1.31(m,3H).

[0208] Intermediate 7: (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0209]

[0210] Step 1: Add hydrogen chloride (4M dioxane solution, 7.86 mL, 31.46 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (200 mg, 0.26 mmol) in acetonitrile (2.00 mL). Stir the solution at 25 °C for 48 hours. The reaction solution was concentrated under vacuum, and the residue was purified by rapid column chromatography (silica gel, 0-15% gradient methanol / dichloromethane) to give a brown solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-ol (157 mg, 0.26 mmol, 99% yield). LCMS (ESI): [M+H] + =603.2

[0211] Step 2: Diisopropylethylamine (123 μL, 0.69 mmol) was added to a solution of compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-ol (140 mg, 0.23 mmol) in dichloromethane (1.4 mL). Trifluoromethanesulfonic anhydride (39.0 μL, 0.23 mmol) was slowly added dropwise at -78 °C, and the solution was stirred at -70 °C for 4 hours. After the reaction was complete, the mixture was quenched with water (1 mL), extracted with dichloromethane (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to give a yellow solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-yltrifluoromethanesulfonate (49.0 mg, 0.07 mmol, yield 29%). LCMS (ESI): [M+H + =735.2.

[0212] Step 3: Under nitrogen protection, compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-yltrifluoromethanesulfonate (45.0 mg, 61.09 μmol), palladium acetate (4.11 mg, 18.33 μmol), and triphenylphosphine (9.64 mg, 36.65 μmol) were added to N,N-dimethylformamide (2.25 mL), followed by the addition of triethylamine (25.5 μL, 0.18 mmol) and formic acid (6.91 μL, 0.18 mmol). The solution was stirred at 80 °C for 30 minutes. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (1 mL), and extracted with ethyl acetate (1 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to give a brown solid compound (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphthyl[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (27.0 mg, 45.87 μmol, yield 75%). LCMS (ESI): [M+H + =587.3.

[0213] Intermediate 8: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0214]

[0215] Step 1: Add cesium fluoride (2431.1 mg, 16.00 mmol) to a solution of tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1370.0 mg, 1.60 mmol) in N,N-dimethylformamide (27 mL). Stir the mixture at 25 °C for 1 hour under nitrogen protection. Dilute with water (90 mL), extract with ethyl acetate (90 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a brown solid compound, tert-butyl(1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (720.0 mg, 1.03 mmol, yield 64%). LCMS (ESI): [M+H] + =700.2.

[0216] Step 2: In a glove box, add tetra(triphenylphosphine)palladium (165.2 mg, 0.14 mmol) and cuprous iodide (13.6 mg, 0.07 mmol) to a solution of tert-butyl(1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,22-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (500.0 mg, 0.71 mmol) and methyl 3-iodoacrylate (227.2 mg, 1.07 mmol) in N,N-dimethylformamide (3.75 mL) and triethylamine (2.5 mL). Stir the mixture at 50 °C for 2 hours under nitrogen protection and then evaporate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a brown solid compound, tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-((E)-5-methoxy-5-oxopent-3-en-1-yn-1-yl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (530.0 mg, 0.68 mmol, 95% yield). LCMS (ESI): [M+H] + =784.2.

[0217] Step 3: Platinum dioxide (400.0 mg, 1.76 mmol) was added to a methanol (50 mL) solution of tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-((E)-5-methoxy-5-oxopent-3-en-1-yn-1-yl)-3-(methoxymethoxy)naphthyl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (500.0 mg, 0.64 mmol). The mixture was stirred at 25 °C for 2 days under a hydrogen atmosphere at 15 psi. The mixture was filtered, and the solid was washed with methanol (50 mL). The filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A yellow solid compound, tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-(5-methoxy-5-oxopentyl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, was obtained (260.0 mg, 0.33 mmol, yield 48%). LCMS (ESI): [M+H] + =790.4.

[0218] Step 4: A solution of tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-(5-methoxy-5-oxopentyl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (240 mg, 0.30 mmol) in tetrahydrofuran (2.4 mL) was added to lithium hydroxide (38.3 mg, 0.91 mmol) and water (0.48 mL). The mixture was stirred at 50 °C for 24 hours. Dilute with water (5 mL), adjust pH to 5-6 with 1 M hydrochloric acid, then extract with ethyl acetate (5 mL * 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to obtain the crude compound 5-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)valeric acid (240 mg), which is a yellow solid. LCMS (ESI): [M + H] + =776.3.

[0219] Step 5: To a solution of 5-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)valeric acid (210 mg, 0.27 mmol) and N-methylmorphorline (273.4 mg, 2.71 mmol) in N-methylpyrrolidone (20 mL), add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (308.8 mg, 0.81 mmol). The mixture was stirred at 25 °C for 2 hours under nitrogen protection, and then stirred at 80 °C for 16 hours. Add water (30 mL) and saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (60 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Purify the residue by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A brown oily crude product (300 mg) is given. Then, the crude product (200 mg) is purified by rapid column chromatography (C18, 0-70% gradient of acetonitrile / water). A white solid compound, tert-butyl(1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, was obtained (72 mg, 0.10 mmol, yield 53%). LCMS (ESI): [M+H] + =758.2.

[0220] Step 6: Add polymethylsiloxane (500 μL) to a solution of tert-butyl(1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (50 mg, 0.07 mmol) and tris(pentafluorophenyl)borane (33.8 mg, 0.07 mmol) in toluene (2 mL). Stir the mixture at 110 °C for 2 days under nitrogen protection. Dry by rotary evaporation. Purify the residue by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A yellow solid compound, tert-butyl(1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester, was obtained (30 mg, 0.04 mmol, yield 61%). LCMS (ESI): [M+H] + =744.3.

[0221] Intermediate 9: (2,2-Difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0222]

[0223] Step 1: 1-(tert-butyl)-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylic acid ester (9.00 g, 33.9 mmol) was dissolved in tetrahydrofuran (90 mL). The temperature was lowered to -78 °C, and bis(trimethylsilyl)aminolithium (1 M tetrahydrofuran, 68.0 mL, 68.0 mmol) was added under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 hour. 3-chloro-2-(chloromethyl)prop-1-ene (12.7 g, 102 mmol) was added to the reaction solution, and the reaction solution was stirred at 20 °C for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL * 3), and the combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-5% gradient tetrahydrofuran / petroleum ether) to give a colorless oily compound 1-(tert-butyl)-2-methyl-2-(2-(chloromethyl)allyl)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid ester (8.90 g, 25.2 mmol, yield 74%). LCMS (ESI): [M-56+H] + =298.0; 1H NMR (400MHz, CDCl3) δppm5.52-5.38(m,1H),5.11(br s,1H),4.13-3.87(m,3H),3.84-3.63(m,4H),3.46-3.21(m,1H),2.86-2.45(m,3H),1.52-1.43(m,9H).

[0224] Step 2: Compound 1-(tert-butyl)-2-methyl-2-(2-(chloromethyl)allyl)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid ester (2.00 g, 5.65 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (6.30 mL, 84.8 mmol) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and adjusted to alkalinity with triethylamine. The solution was then concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient to methanol / dichloromethane) to give a yellow oily compound methyl 2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid (0.50 g, 2.26 mmol, yield 40%). LCMS (ESI): [M+H] + =218.1; 1 ¹H NMR (400MHz, CDCl₃) δppm 5.01–4.95 (m, 2H), 3.91 (brd, J = 14.6Hz, 1H), 3.70 (s, 3H), 3.60–3.49 (m, 1H), 3.47–3.34 (m, 2H), 3.00–2.82 (m, 2H), 2.65 (brd, J = 16.4Hz, 1H), 2.44–2.29 (m, 1H). Lithium aluminum hydride (2.5M tetrahydrofuran solution, 4.00 mL, 10.0 mmol) was dissolved in tetrahydrofuran (4 mL). Methyl 2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (500 mg, 2.26 mmol) was added at 0 °C. The reaction mixture was stirred at 60 °C for 2 hours. Water (370 μL), sodium hydroxide (15% aqueous solution, 370 μL), and water (1000 μL) were added to the reaction solution for quenching. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (220 mg, 1.13 mmol, yield 50%). LCMS (ESI): [M+H] + =182.1.

[0225] Intermediate 10: (hexahydrocyclopropane[b]pyrrolazine-5a(3H)-yl)methanol

[0226]

[0227] Step 1: Under a nitrogen atmosphere at -65°C, lithium bis(trimethylsilylamino)carboxylate (950 mg, 3.72 mmol) in tetrahydrofuran (10 mL) of (3R)-2-tert-butyl-3-ethyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (10 mL) and 1-bromo-3-chloropropane (1.76 g, 11.16 mmol) was added (10 mL). The reaction was stirred at 25°C for 16 hours. A saturated ammonium chloride solution (10 mL) was added to the mixture, followed by extraction with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / dichloromethane) to give a colorless oily compound, 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid ester (630 mg, 1.90 mmol, yield 51%). LCMS (ESI): [M+Na] + =354.3.

[0228] Step 2: Hydrogen chloride (4M dioxane solution, 1.38 mL, 5.51 mmol) was added to a solution of 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid ester (610 mg, 1.84 mmol) in dichloromethane (6 mL). The reaction was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum to give a colorless, oily crude compound, ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ester (60% purity, 690 mg). LCMS (ESI): [M+H] + =232.2.

[0229] Step 3: Potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol) were added to an ethanol (26 mL) solution of ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 670 mg, 1.73 mmol). The reaction was stirred at 25 °C for 16 hours. The mixture was filtered and concentrated. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient ethanol / dichloromethane) to give a yellow oily compound, hexahydrocyclopropane[b]pyrrolizine-5a(3H)-carboxylate (95% purity, 320 mg, 1.56 mmol, 90% yield). LCMS (ESI): [M+H] + =196.1.

[0230] Step 4: At 0°C, lithium aluminum hydride (72 mg, 1.91 mmol) was added to a tetrahydrofuran (3 mL) solution of ethyl hexahydrocyclopropano[b]pyrrolizin-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol). The mixture was stirred at 0°C for 1 hour. Water (72 μL) and a 15% sodium hydroxide aqueous solution (72 μL) were added to the reaction mixture, followed by the addition of water (216 μL). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered and the filter cake was washed with tetrahydrofuran (30 mL). The filtrate was concentrated under vacuum to give the crude compound (hexahydrocyclopropano[b]pyrrolizin-5a(3H)-yl)methanol (230 mg), a yellow oily liquid. LCMS (ESI): [M+H] + =154.1.

[0231] Intermediate 11: (1-morpholinocyclopropyl)methanol

[0232]

[0233] Step 1: 1-Aminocyclopropane-1-carboxylate ethyl ester (200 mg, 1.55 mmol) was dissolved in acetonitrile (2.00 mL), and potassium carbonate (899 mg, 6.50 mmol) and tetrabutylammonium bromide (74.9 mg, 0.23 mmol) were added. Then, an acetonitrile solution of 1-bromo-2-(2-bromoethoxy)ethane (431 mg, 1.86 mmol) was added dropwise to the above reaction solution. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was purified by rapid column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give a colorless oily compound, 1-morpholinocyclopropane-1-carboxylate ethyl ester (160 mg, 0.81 mmol, yield 52%). 1 H NMR (400MHz, CDCl3) δppm 4.15 (q, J = 7.1Hz, 2H), 3.59 (br s, 4H), 2.96 (brs, 4H), 1.36-1.18 (m, 5H), 0.94 (q, J = 3.7Hz, 2H).

[0234] Step 2: At 0°C, lithium aluminum hydride (0.64 mL, 1.61 mmol) was added to a solution of ethyl 1-morpholinocyclopropane-1-carboxylate (160 mg, 0.80 mmol) in tetrahydrofuran (1.50 mL). The mixture was stirred at 0°C for 1 hour. Water (0.64 mL) and a 15% sodium hydroxide aqueous solution (0.64 mL) were added to the reaction mixture, followed by the addition of water (1.92 mL). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered and the filter cake was washed with tetrahydrofuran (30 mL). The filtrate was concentrated under vacuum to give crude compound (1-morpholinocyclopropyl)methanol (100 mg), which was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δppm 3.68-3.62(m,4H),3.59(s,2H),2.80-2.64(m,4H),0.76-0.70(m,2H),0.56-0.50(m,2H).

[0235] Intermediate 12: (2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and (2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0236]

[0237] Step 1: At -50°C, add a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (1.0 g, 4.73 mmol) and a solution of 2-((difluoromethyl)sulfonyl)pyridine (0.82 g, 4.26 mmol) in N,N-dimethylformamide (5 mL) to a solution of potassium tert-butoxide (0.95 g, 8.52 mmol) in N,N-dimethylformamide (5 mL). Slowly heat the mixture to 25°C under nitrogen protection and stir at 25°C for 0.5 hours. Under ice bath conditions, add a saturated ammonium chloride solution (5 mL) and 2M hydrochloric acid (9 mL), then add water (30 mL). Extract with ethyl acetate (30 mL x 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to give a yellow oily compound, ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (250 mg, 1.02 mmol, yield 22%). LCMS (ESI): [M+H] + =246.0; 1 H NMR (400MHz, CDCl3) δppm 4.36 (br d, J=14.7Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.75 (br d,J=14.7Hz,1H),3.13(td,J=1.3,15.4Hz,1H),2.90-2.73(m,1H),2.63(ddd,J=2.0,9. 2,13.2Hz,1H),2.55-2.34(m,2H),2.15(td,J=10.1,13.2Hz,1H),1.29(t,J=7.2Hz,3H).

[0238] Step 2: At 0°C, add a solution of 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (100.0 mg, 0.41 mmol) in tetrahydrofuran (1 mL) to a solution of lithium aluminum hydride (15.5 mg, 0.41 mmol) in tetrahydrofuran (1 mL). Stir the mixture at 65°C for 5 hours, then add lithium aluminum hydride (7.7 mg, 0.20 mmol) and stir at 65°C for 3 hours. The mixture was cooled to 0°C, and water (23 μL), 15% sodium hydroxide (23 μL), and water (69 μL) were added. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a yellow, oily crude compound, a mixture (74.0 mg) of (2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and (2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol. LCMS (ESI): [M+H] + =190.1; 172.1.

[0239] Example 1: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-5,6-dihydro-4H-naphtho[1',8':4,5,6]acodecin[2,3-g]quinazolin-7(8H)-one

[0240]

[0241] Step 1: At 25°C, tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane Sodium tert-butoxide (79.0 mg, 0.80 mmol) was added to a tetrahydrofuran (2.00 mL) solution of 8-carboxylic acid ester (80% purity, 150 mg, 0.16 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (77.1 mg, 0.48 mmol). The reaction system was then reacted at 50 °C for 16 hours. The reaction solution was cooled to room temperature, quenched with water (3 mL), and extracted with ethyl acetate (3 mL * 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-8% gradient of methanol / dichloromethane) to give a yellow solid compound tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-7-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecano[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40.0 mg, 0.05 mmol, yield 30%). LCMS (ESI): [M+H] + =802.9

[0242] Step 2: At 25°C, hydrogen chloride (4M dioxane solution, 200 μL, 0.80 mmol) was added to an acetonitrile (800 μL) solution of tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-7-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40.0 mg, 0.05 mmol). The reaction system was reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was added to acetonitrile (4 mL), and the pH was adjusted to 8 with triethylamine. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid compound 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-5,6-dihydro-4H-naphtho[1',8':4,5,6]acecanoin[2,3-g]quinazolin-7(8H)-one (7.68 mg, 11.6 μmol, yield 26%). LCMS (ESI): [M+H] + =659.3. 1 H NMR (400MHz, CD3OD) δppm7.80(s,1H),7.70(dd,J=6.1,9.0Hz,1H),7.32-7.20(m,2H),6.91(s,1H),5.46-5.24(m,1H),4.65(br d,J=12.3Hz,1H),4.44-4.19(m,3H),3.77(br d,J=12.7Hz,1H),3.71-3.57(m,3H),3.31-3.19(m,3H),3.05(dt,J=6.1,9.3Hz,1H),2.97-2.87(m,1H),2.76(br t,J=12.2Hz,1H),2.46-2.23(m,3H),2.22-2.15(m,1H),2.14-2.08(m,1H),2.08-1.98(m,4H),1.95-1.83(m,4H),1.82-1.74(m,1H).

[0243] Example 2: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acodecin[2,3-g]quinazolin-16-ol

[0244]

[0245] Step 1: Tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (150 mg, 0.20 mmol), tris(pentafluorophenyl)borane (206 mg, 0.40 mmol) and polymethylsiloxane (2.50 mL, 1.00 mmol) were added to toluene (6.00 mL), and the reaction mixture was stirred at 110 °C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (silica gel, 0-30% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound, tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecanoin[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (140 mg, 0.19 mmol, yield 95%). LCMS (ESI): [M+H] + =730.2.

[0246] Step 2: Dissolve tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (140 mg, 0.19 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (91.6 mg, 0.58 mmol) in tetrahydrofuran (2.00 mL), then add sodium tert-butoxide (55.3 mg, 0.58 mmol), and stir the reaction solution at 60 °C for 24 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (1 mL) and water (1 mL) to separate the organic layer. The aqueous layer was extracted with ethyl acetate (1 mL * 2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to give a yellow solid compound tert-butyl(1R,5S)-3-(3,14-difluoro-12-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (48.0 mg, 0.06 mmol, yield 32%). LCMS(ESI): [M+H + =789.5.

[0247] Step 3: Dissolve tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (46.0 mg, 0.06 mmol) in acetonitrile (2.00 mL), add hydrogen chloride (4 M dioxane solution, 292 μL, 1.17 mmol), and stir at 25 °C for 2 hours. The reaction solution was concentrated under vacuum. The residue was added to acetonitrile (1 mL), neutralized with triethylamine to pH > 7, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a yellow solid 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecanoin[2,3-g]quinazolin-16-ol (18.4 mg, 0.03 mmol, yield 49%). LCMS (ESI): [M+H] + =645.4. 1 H NMR(400MHz,CD3OD)δppm 7.78-7.70(m,1H),7.36-7.24(m,2H),7.08(s,1H),7.04-6.99(m,1H),5.41-5.26(m,1H) ,4.45-4.34(m,2H),4.32-4.26(m,1H),4.24-4.18(m,1H),3.71-3.52(m,4H),3.47-3.38( m,1H),3.28-3.22(m,3H),3.10-2.98(m,1H),2.87-2.75(m,1H),2.61-2.49(m,1H),2.44- 2.13(m,3H),2.07-1.98(m,2H),1.97-1.85(m,6H),1.70-1.53(m,2H),1.41-1.03(m,2H).

[0248] Example 3: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-16-ol

[0249]

[0250] Step 1: Add cesium carbonate (13.0 mg, 40.70 μL) and methyl iodide (4.59 μL, 74.33 μL) to a dimethylformamide (200 μL) solution of tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acodecino[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (27.0 mg, 37.0 μL) and stir at 25 °C for 16 hours. The reaction solution was slowly poured into ice water (100 μL), and ethyl acetate (100 μL) was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 μL * 2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by rapid column chromatography (silica gel, 0-40% gradient tetrahydrofuran / petroleum ether) to give a yellow solid compound tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-methyl-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (22.0 mg, 29.58 μmol, yield 80%). LCMS(ESI):[M+H] + =744.3.

[0251] Step 2: Add tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-methyl-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20.0 mg, 26.89 μmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (12.8 mg, 80.67 μmol) to tetrahydrofuran (400 μL), then add sodium tert-butoxide (7.75 mg, 80.67 μmol), and stir at 60 °C for 6 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (200 μL) and water (200 μL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 μL * 2). The organic layers were combined, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a brown oily compound, tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceconitin[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20.0 mg, 24.90 μmol, yield 93%). LCMS(ESI):[M+H] + =803.5.

[0252] Step 3: Dissolve tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]aceceno[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20.0 mg, 24.90 μmol) in acetonitrile (400 μL), add hydrogen chloride (4 M dioxane solution, 62.3 μL, 0.25 mmol), and stir at 25 °C for 2 hours. The reaction solution was concentrated under vacuum, and the residue was added to acetonitrile (500 μL). The mixture was neutralized with triethylamine to pH > 7, and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative HPLC to give a yellow solid 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecanoin[2,3-g]quinazolin-16-ol (9.40 mg, 14.19 μmol / mmol, yield 57%). LCMS (ESI): [M+H] + =659.3. 1 H NMR (400MHz, CD3OD) δppm 7.65 (dd, J=6.0, 9.0Hz, 1H), 7.41 (s, 1H), 7.26-7.18 (m, 2H), 6.94 (d, J=2.4Hz, 1H), 5.41-5.23 (m, 1H), 4.48 (br dd,J=6.3,12.8Hz,1H),4.37(br d,J=15.5Hz,1H),4.32-4.26(m,1H),4.24-4.18(m,1H),3.71-3.54(m,4H),3.32-3.15(m,3H),3.09-2 .96(m,1H),2.95-2.73(m,2H),2.40(s,3H),2.37-2.12(m,4H),2.06-1.83(m,8H),1.52-1.29(m,4H).

[0253] Example 4: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one

[0254]

[0255] Step 1: Add sodium tert-butoxide (25.4 mg, 0.26 mmol) to a solution of tert-butyl(1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.13 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (63.0 mg, 0.40 mmol) in tetrahydrofuran (2 mL). Stir the mixture at 50 °C for 24 hours under nitrogen protection. The reaction solution was cooled to 0°C and diluted with water (5 mL). Extraction was performed using ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude compound tert-butyl(1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-8-oxo-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (140 mg), which was a brown oily liquid. LCMS(ESI): [M+H] + =817.6.

[0256] Step 2: Add hydrogen chloride (4M dioxane solution, 550 μL, 2.20 mmol) to a solution of tert-butyl(1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-8-oxo-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (120 mg, 0.15 mmol) in acetonitrile (2400 μL). Stir the solution at 25 °C for 1 hour. The solution was dried under nitrogen, and the residue was purified by preparative HPLC to give a white solid compound 11-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one (6.76 mg, 0.01 mmol, yield 7%). LCMS (ESI): [M+H] + =673.2. 1 H NMR(400MHz,CD3OD)δppm 7.82(s,1H),7.67(dd,J=5.9,9.0Hz,1H),7.34-7.19(m,2H),6.94(d,J=2.3Hz,1H),5.40-5.23(m,1H), 4.49-4.42(m,2H),4.33-4.18(m,2H),3.83-3.59(m,4H),3.29-3.19(m,3H),3.08-2.98(m,1H),2.75(br s,1H),2.59-2.40(m,2H),2.36-2.20(m,2H),2.13(d,J=9.2Hz,2H),2.06-1.77(m,8H),1.58-1.41(m,3H).

[0257] Example 5: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0258]

[0259] Step 1: Add sodium tert-butoxide (3.8 mg, 0.04 mmol) to a solution of tert-butyl(1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (15 mg, 0.02 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (9.6 mg, 0.06 mmol) in tetrahydrofuran (0.3 mL). Stir the mixture at 50 °C for 24 hours under nitrogen protection. The solution was diluted with water (2 mL) at 0 °C, extracted with ethyl acetate (5 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude compound tert-butyl(1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20 mg), which was a brown oily liquid. LCMS(ESI): [M+H] + =803.4.

[0260] Step 2: Add hydrogen chloride (4M dioxane solution, 75 μL, 0.30 mmol) to a solution of tert-butyl(1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (20 mg, 0.02 mmol) in acetonitrile (400 μL). Stir the solution at 25 °C for 1 hour. Dry the solution with nitrogen. The residue was purified by preparative HPLC to give a white solid compound 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol (2.03 mg, 3.0 μmol, yield 15%). LCMS (ESI): [M+H] + =659.3. 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.69(dd,J=5.8,9.0Hz,1H),7.31(d,J=2.6Hz,1H),7.25(t,J=9.5Hz,1H),7.06(s,1H),6.94(d,J=2.6Hz,1H),5.43-5.28(m,1H),4.48(br d,J=12.0Hz,1H),4.41-4.23(m,3H),3.78(br s,2H),3.72-3.55(m,3H),3.38(br s,2H),3.18-2.93(m,2H),2.64(br d,J=11.9Hz,1H),2.48-2.26(m,3H),2.19(br d,J=11.5Hz,1H),2.13-1.86(m,8H),1.78-1.49(m,3H),1.46-1.29(m,3H).

[0261] Example 6A: 3,15-Difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol

[0262] Example 6B: 3,15-Difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol

[0263]

[0264] Step 1: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one (80 mg, 0.12 mmol) and 1,5-cyclooctadiene iridium chloride dimer (8.13 mg, 0.01 mmol) in tetrahydrofuran (12 mL), phenylsilane (262.1 mg, 2.42 mmol) was added. The mixture was stirred at 55 °C for 10 hours under nitrogen protection and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to give a yellow solid (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (24 mg, 0.04 mmol, yield 31%). LCMS (ESI): [M+H + =647.2.

[0265] Step 2: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (43 mg, 0.07 mmol) in N,N-dimethylformamide (1.075 mL), cesium carbonate (23.8 mg, 0.07 mmol) and methyl iodoformate (8.2 μL, 0.13 mmol) were added. The mixture was stirred for 16 hours under nitrogen protection and at 25 °C. Dilute with water (3 mL), extract with ethyl acetate (5 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to give the crude compound (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (62 mg). LCMS (ESI): [M+H + =661.3.

[0266] Step 3: Add sodium tert-butoxide (26.2 mg, 0.27 mmol) to a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (60 mg, 0.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57.8 mg, 0.36 mmol) in tetrahydrofuran (1.5 mL). Stir the mixture at 60 °C for 12 hours under nitrogen protection. Dilute with water (3 mL), extract with ethyl acetate (3 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to give crude compound (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (100 mg), which is a brown oily liquid. LCMS(ESI): [M+H] + =720.4.

[0267] Step 4: Add hydrogen chloride (4M dioxane solution, 520 μL, 2.08 mmol) to a solution of (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (100 mg, 0.09 mmol) in acetonitrile (2000 μL). Stir the solution at 25 °C for 1 hour. Dry the solution with nitrogen. The residue was purified by preparative HPLC to give two isomers of compound 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol.

[0268] Example 6A: LCMS(ESI): [M+H] + =676.4. 1 H NMR(400MHz,CD3OD)δppm 7.84(s,1H),7.66(dd,J=5.9,9.0Hz,1H),7.29-7.17(m,2H),6.90(d,J=2.6Hz,1H),5.48-5.26(m,1H),4.47-4.26(m,3H),4.15(br d,J=13.4Hz,1H),3.52-3.35(m,4H),3.21-3.11(m,1H),2.95-2.84(m,1H),2.78(s,3H ),2.69-2.44(m,3H),2.40-2.32(m,1H),2.28-2.05(m,4H),2.03-1.65(m,6H),1.58(br s,1H),1.47-1.18(m,8H).

[0269] Example 6B: LCMS(ESI): [M+H] + =676.4. 1H NMR(400MHz,CD3OD)δppm 7.80(s,1H),7.66(dd,J=5.9,9.0Hz,1H),7.29-7.17(m,2H),6.90(d,J=2.6Hz,1H),5.49-5.26(m,1H),4.45-4.38(m,1H ),4.33(d,J=11.3Hz,2H),4.18(d,J=13.3Hz,1H),3.47-3.36(m,4H),3.28(d,J=3.3Hz,1H),3.19-3.10(m,1H),2.91(br t,J=10.1Hz,1H),2.80(s,3H),2.59(br d,J=6.4Hz,2H),2.39-2.31(m,1H),2.27-2.15(m,2H),2.15-2.03(m,2H),2.01-1.64(m,6H),1.54(br s,1H),1.43-1.24(m,8H).

[0270] Example 7: (R)-1-(3,15-difluoro-13-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0271]

[0272] Step 1: Add sodium tert-butoxide (15.7 mg, 0.16 mmol) to a solution of (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (32 mg, 0.05 mmol) and (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (30.8 mg, 0.22 mmol) in tetrahydrofuran (0.8 mL). Stir the mixture under nitrogen protection at 60 °C for 30 hours. Dilute with water (2 mL), extract with ethyl acetate (3 mL x 3), dry the combined organic phases to anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by preparative HPLC to give a yellow solid compound (R)-1-(3,15-difluoro-13-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (5.81 mg, 9.2 μmol, yield 14%). LCMS (ESI): [M+H + =628.2. 1 H NMR (400MHz, CD3OD) δppm 8.06 (d, J=8.1Hz, 1H), 7.94 (dd, J=6.0, 9.0Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.50-7.29 (m, 3H), 4.38 (br s, 2H), 4.24 (br d,J=13.3Hz,1H),4.17-4.06(m,1H),3.83-3.70(m,1H),3.45-3.38(m,1H),3.29(br s,1H),3.06-2.85(m,3H),2.77-2.65(m,1H),2.48(br d,J=5.5Hz,1H),2.16(br dd,J=6.4,12.4Hz,3H),2.09-1.93(m,4H),1.92-1.71(m,7H),1.59(br d,J=8.1Hz,2H),1.43(br s,2H),1.32(br d,J=3.1Hz,4H),1.02(br s,1H).

[0273] Example 8: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-18-ol

[0274]

[0275] Step 1: At 25°C, copper iodide (7.80 mg, 0.04 mmol), iodine (313 mg, 1.23 mmol), and dichlorobis(triphenylphosphine)palladium(II) (28.8 mg, 0.04 mmol) were slowly added to a toluene / diisopropylamine (v / v = 1:1, 4.5 mL) solution of tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl) and 4-tert-butyldimethylsiloxybutyne (424 μL, 2.06 mmol) in 25°C. The reaction was stirred at 25°C for 16 hours. Add 3 mL of saturated sodium sulfite aqueous solution to the reaction mixture, extract with ethyl acetate (3 mL * 2), wash the organic phase with water (3 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-40% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound tert-butyl(1R,5S)-3-(7-(8-(6-((tert-butyldimethylsilyl)oxy)hex-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy))naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (364 mg, 0.40 mmol, yield 97%). LCMS (ESI): [M+H] + =912.4.

[0276] Step 2: Under nitrogen protection, platinum dioxide (100 mg) was added to a methanol (1 mL) solution of tert-butyl(1R,5S)-3-(7-(8-(6-((tert-butyldimethylsilyl)oxy)hex-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy))naphthyl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.11 mmol). The solution was purged with hydrogen and stirred at 20 °C for 16 hours under a hydrogen atmosphere of 15 psi. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude compound tert-butyl(1R,5S)-3-(6-amino-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (110 mg), which was a brown solid. LCMS (ESI): [M+H] + =890.4.

[0277] Step 3: At 0°C, sodium bicarbonate (56.6 mg, 0.67 mmol) was added to a tetrahydrofuran (4 mL) solution of tert-butyl(1R,5S)-3-(6-amino-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (300 mg, 0.34 mmol). The solution was stirred at 0°C for 5 minutes. While maintaining at 0°C, benzyl chloroformate (95.0 μL, 0.67 mmol) was added to the reaction mixture. The reaction was stirred at 25°C for 16 hours. The reaction mixture was added to water (5 mL), extracted with ethyl acetate (3 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (400 mg), which was a brown solid. LCMS (ESI): [M + H] + =1024.5.

[0278] Step 4: At 20°C, tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (400.0 mg, 0.39 mmol) was dissolved in tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 8.0 mL, 8.0 mmol). The reaction was stirred at 20°C for 1 hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give a pale yellow solid compound, tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (240 mg, 0.26 mmol, yield 68%). LCMS (ESI): [M+H] + =910.4.

[0279] Step 5: Under a nitrogen atmosphere at 20°C, triphenylphosphine (553 mg, 2.11 mmol) and diisopropyl azodicarbonate (780 μL, 3.96 mmol) were slowly added to tetrahydrofuran (8 mL) containing tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (240 mg, 0.26 mmol). The reaction was stirred at 65°C for 1 hour. Water (8 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (6 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give a pink oily compound benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-18-(methoxymethoxy)-14-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylic acid ester (40% purity, 200 mg, 0.09 mmol, yield 34%). LCMS (ESI): [M+H + =892.5.

[0280] Step 6: At 0°C, the compound benzyl12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-18-(methoxymethoxy)-14-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2 A solution of quinazoline-10-carboxylic acid ester (180 mg, 0.08 mmol) in tetrahydrofuran (3 mL) was reacted with 180 mg of 4A molecular sieve, 102 mg of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (102 mg, 0.65 mmol), and 62.0 mg of sodium tert-butoxide (0.65 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with 4 mL of water, extracted with ethyl acetate (3 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient methanol / dichloromethane) to give a yellow oily compound benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylic acid ester (60.0 mg, 0.06 mmol, yield 78%). LCMS (ESI): [M+H] + =951.7.

[0281] Step 7: Under nitrogen protection, at 25°C, wet palladium on carbon (55.0 mg) was added to a 2 mL solution of benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylic acid ester (55.0 mg, 0.06 mmol). The solution was stirred at 20°C and under a hydrogen atmosphere of 15 psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid compound, tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40.0 mg, 0.05 mmol, yield 85%). LCMS (ESI): [M+H] + =817.2.

[0282] Step 8: At 25°C, add hydrogen chloride (4M dioxane solution, 214.0 μL, 0.86 mmol) to a solution of tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (35.0 mg, 0.04 mmol) in acetonitrile (1 mL). Stir the solution at 20°C for 1 hour. Quench the solution with triethylamine (200 μL) and concentrate. The residue was purified by preparative HPLC to give a yellow solid compound 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclic dodecano[2,3-g]quinazolin-18-ol (formate, 4.59 mg, 6.55 μmol, yield 15%). LCMS (ESI): [M+H] + =673.2. 1 H NMR (400MHz, CD3OD) δppm8.52(br s,1H),7.65(dd,J=8.9,5.9Hz,1H),7.33-7.18(m,2H),6.94(br s,2H),5.48-5.29(m,1H),4.50(br d,J=12.6Hz,1H),4.46-4.32(m,3H),3.95(br s,2H),3.73-3.59(m,3H),3.54(br s,3H),3.22(br d,J=11.74Hz,1H),2.76-2.63(m,1H),2.52-1.92(m,12H),1.77(br s,1H),1.56-1.39(m,3H),1.27-1.16(m,3H),1.07(br d,J=6.6Hz,1H).

[0283] Examples 9A and 9B: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-9(10H)-one

[0284]

[0285] Step 1: Under a nitrogen atmosphere at 20°C, slowly add Dysmart oxidant (652.0 mg, 1.53 mmol) to a solution of tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (700.0 mg, 0.77 mmol) in dichloromethane (7.00 mL). The reaction is stirred at 20°C for 3 hours. The reaction mixture was added to a saturated sodium bicarbonate solution (4 mL) and water (6 mL), and extracted with ethyl acetate (5 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(6-oxohexyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.00 g), which was a yellow oily liquid. LCMS(ESI): [M+H] + =908.3.

[0286] Step 2: At 0°C, 2-methyl-2-butene (2.33 mL, 22.03 mmol), sodium dihydrogen phosphate (0.66 g, 5.51 mmol), and sodium chlorite (0.50 g, 5.51 mmol) were slowly added to a solution of tert-butyl(1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(6-oxohexyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (1.00 g, 1.10 mmol) in tert-butanol (6.00 mL) and water (3.00 mL). The reaction was stirred at 20°C for 2 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated sodium bicarbonate (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-25% gradient tetrahydrofuran / petroleum ether) to give a yellow solid compound 6-(8-(6-((benzyloxy)carbonyl)amino)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)hexanoic acid (620.0 mg, 0.67 mmol, yield 60%). LCMS (ESI): [M+H + =924.3.

[0287] Step 3: At 20°C, dry palladium on carbon (620.0 mg) was added to a 5.00 mL solution of ethyl acetate containing 6-(8-(6-((benzyloxy)carbonyl)amino)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)hexanoic acid (620.0 mg, 0.67 mmol). The solution was stirred at 20°C under a hydrogen atmosphere of 15 psi for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-20% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)hexanoic acid (500.0 mg, 0.63 mmol, yield 94%). LCMS (ESI): [M+H] + =790.3.

[0288] Step 4: At 20°C, slowly add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (806.2 mg, 5.06 mmol) and sodium tert-butoxide (365.0 mg, 3.79 mmol) to a tetrahydrofuran (7.00 mL) solution of compound 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)hexanoic acid (500.0 mg, 0.63 mmol) and 4A powdered molecular sieve (500.0 mg) to the solution. Stir the solution at 80°C for 16 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)hexanoic acid (1.00 g), which was a brown oily liquid. LCMS(ESI): [M+H] + =849.4.

[0289] Step 5: At 20°C, diisopropylethylamine (8.39 mL, 47.12 mmol) and tri-n-butylcyclophosphine (3.50 mL, 5.88 mmol) were slowly added to a solution of 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)hexanoic acid (1.00 g, 1.17 μmol) in dioxane (40.0 mL) and tri-n-butylcyclophosphine (50% ethyl acetate solution, 3.50 mL, 5.88 mmol) were added. The solution was stirred at 100°C for 2 hours. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid compound, tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-9-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-12-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid ester (0.80 g, 0.96 μmol, yield 82%). LCMS (ESI): [M+H] + =831.4.

[0290] Step 6: At 20°C, add hydrogen chloride (4 M dioxane solution, 4.81 mL, 19.2 mmol) to a solution of tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-9-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-12-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid ester (0.80 g, 0.96 μmol) in acetonitrile (10.0 mL). Stir the solution at 20°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was neutralized with triethylamine (200 μL) in dimethyl sulfoxide (3 mL). The mixture was purified by preparative HPLC to give a yellow solid compound 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-9(10H)-one (Example 10) (43.03 mg, 0.06 μmol, yield 6%). LCMS (ESI): [M+H + =687.2. 1 HNMR(400MHz,CH3OD)δppm 8.94-7.75(m,1H),7.68(dd,J=9.0,5.8Hz,1H),7.34-7.19(m,2H),6.91(br s,1H),5.38-5.18(m,1H),4.66-4.39(m,2H),4.29-4.14(m,2H),3.66(br s,4H),3.19(br d,J=19.1Hz,3H),3.06-2.74(m,3H),2.39-2.05(m,4H),2.03-1.81(m,9H),1.52-0.71(m,5H).

[0291] Example 9: Two stereoisomers were obtained by SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / isopropanol; phase B is maintained at 60%; flow rate: 80 mL / min).

[0292] Example 9A: LCMS(ESI): [M+H] +=687.2; SFC analysis (column: Chiralpak IG-3 50*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / isopropanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position is 1.861 min; 1 H NMR(400MHz,CD3OD)δppm 9.15-7.90(m,1H),7.68(dd,J=8.9,5.9Hz,1H),7.35-7.19(m,2H),6.91( s,1H),5.35-5.21(m,1H),4.60-4.39(m,2H),4.31-4.12(m,2H),3.65(br s,4H),3.23-3.12(m,3H),3.05-2.76(m,3H),2.39-2.06(m,4H),2.04-1.75(m,9H),1.52-1.23(m,5H).

[0293] Example 9B: LCMS(ESI): [M+H] + =687.2; SFC analysis (column: Chiralpak IG-3) ID, 3µm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 mL / min; Chiral column elution position is 5.5-20 min; 1 H NMR(400MHz,CD3OD)δppm 9.10-7.98(m,1H),7.67(dd,J=9.11,5.93Hz,1H),7.35-7.19(m,2H),6.90(s,1H),5.35-5.20(m,1H),4.67-4.36(m,2H),4.29- 4.11(m,2H),3.75-3.47(m,4H),3.23-3.14(m,3H),3.04-2.75(m,3H),2.40-2.07(m,4H),2.01-1.76(m,9H),1.50-1.28(m,5H).

[0294] Example 10: 15-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-hydroxy-4,5,6,7,8,9,10,11-octahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-12(13H)-one

[0295]

[0296] Step 1: To a solution of tert-butyl(1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (200 mg, 0.29 mmol), hepta-6-ethynic acid (180.3 mg, 1.43 mmol), and N-methylmorpholine (144.4 mg, 1.43 mmol) in N,N-dimethylacetamide (4 mL), add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (326 mg, 0.86 mmol). The mixture was stirred at 25 °C under nitrogen protection for 1 hour, and then stirred at 60 °C for 16 hours. The mixture was concentrated under pressure, and saturated sodium bicarbonate solution (10 mL) was added. Extraction was performed using ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a yellow solid compound tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-(hept-6-ynamidinamide)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (150 mg, 0.19 mmol, yield 65%). LCMS (ESI): [M+H] + =808.2.

[0297] Step 2: Add iodine (75.4 mg, 0.30 mmol) to a solution of tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-(hept-6-ynamido)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (80.0 mg, 0.10 mmol), bis(triphenylphosphine)palladium dichloride (3.5 mg, 5.0 μmol), and cuprous iodide (1.9 mg, 10.0 μmol) in toluene / diisopropylamine (1:1, 90 mL, v / v). The mixture was stirred at 80°C for 2 hours, then saturated sodium sulfite solution (30 mL) was added, and extraction was performed using ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to give a yellow solid cyclized compound (42.0 mg, 0.05 mmol, yield 53%). LCMS (ESI): [M+H]+ =806.3.

[0298] Step 3: Add 100.0 mg of dry palladium on carbon to a methanol (50 mL) solution of the cyclic compound (58.0 mg, 0.07 mmol) obtained above. Stir the mixture at 25 °C for 16 hours under a hydrogen atmosphere of 15 psi. Filter and wash the solid with methanol (100 mL), then evaporate the filtrate to dryness. The crude compound tert-butyl(1R,5S)-3-(3,19-difluoro-21-(methoxymethoxy)-12-oxo-17-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (56.0 mg) is a brown solid. LCMS(ESI):[M+H] + =814.4.

[0299] Step 4: Add sodium tert-butoxide (19.8 mg, 0.21 mmol) to a solution of tert-butyl(1R,5S)-3-(3,19-difluoro-21-(methoxymethoxy)-12-oxo-17-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (56 mg, 0.07 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.8 mg, 0.28 mmol) in tetrahydrofuran (1.1 mL). The mixture was stirred at 50°C under nitrogen protection for 16 hours. It was diluted with water (2 mL), extracted with ethyl acetate (3 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to give the crude compound tert-butyl(1R,5S)-3-(3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-(methoxymethoxy)-12-oxo-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (120 mg), which was a brown oily liquid. LCMS(ESI):[M+H] + =873.7.

[0300] Step 5: Add hydrogen chloride (4M dioxane solution, 429 μL, 1.72 mmol) to a solution of tert-butyl(1R,5S)-3-(3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-(methoxymethoxy)-12-oxo-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.07 mmol) in acetonitrile (2 mL). Stir the solution at 25 °C for 1 hour. Dry the solution with nitrogen. The residue was purified by preparative HPLC to give a white solid compound 15-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-hydroxy-4,5,6,7,8,9,10,11-octahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-12(13H)-one (formate, 8.90 mg, 0.01 mmol, yield 11%). LCMS (ESI): [M+H] + =729.2. 1 H NMR(400MHz,CD3OD)δppm 9.18(s,1H),8.55(s,1H),7.73(dd,J=5.9,9.0Hz,1H),7.37(d,J=2.5Hz,1H ),7.29(t,J=9.4Hz,1H),6.98(d,J=2.6Hz,1H),5.49-5.21(m,1H),4.65(br d,J=12.9Hz,1H),4.49(br d,J=13.1Hz,1H),4.40-4.27(m,2H),3.89(br s,2H),3.74(br d,J=13.9Hz,1H),3.59(br d,J=13.5Hz,1H),3.52-3.35(m,3H),3.12(dt,J=5.4,9.7Hz,1H),2.90-2.7 2(m,1H),2.58-2.36(m,2H),2.35-2.28(m,2H),2.20-1.95(m,10H),1.49(br s,1H),1.36-1.12(m,10H).

[0301] Example 11: 16-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,20-difluoro-18-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-22-hydroxy-5,6,7,8,9,10,11,12-octahydro-4H-naphtho[1',8':4,5,6][1]azacyclohexadecano[2,3-g]quinazolin-13(14H)-one

[0302]

[0303] Example 11 prepared the following LCMS (ESI): [M+H] using a similar synthetic route as in Example 10. + =743.3; 1 HNMR(400MHz,CD3OD)δppm 9.24(s,1H),7.71(dd,J=5.8,9.1Hz,1H),7.35(d,J=2.6Hz,1H),7.27(t,J=9.6Hz,1H),7.00(d,J=2.6Hz,1H),5.36-5.22(m,1H),4.53(br dd,J=8.3,12.4Hz,2H),4.26(d,J=10.6Hz,1H),4.18(dd,J=2.3,10.2Hz,1H),3.72-3.53(m,4H),3.30-3.11(m,4H),3.00(br d,J=5.1Hz,1H),2.78-2.62(m,1H),2.38-2.33(m,2H),2.25-2.18(m,1H),2.15-2.10(m,1H),2.05(br d,J=4.0Hz,2H),2.02-1.87(m,8H),1.85-1.76(m,2H),1.58(br s,1H),1.45(br d,J=6.2Hz,1H),1.37-1.27(m,2H),1.23-1.15(m,6H).

[0304] Example 12: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]acodecin[3,4-g]quinazolin-8-one

[0305] Example 13: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]aceceno[3,4-g]quinazolin-8-one

[0306]

[0307] Step 1: The compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (150 mg, 0.2 mmol), dibenzylamine (159 mg, 0.8 mmol) and formaldehyde (37% aqueous solution, 48 μL, 0.6 mmol) were dissolved in dimethyl sulfoxide (0.4 mL), and cuprous iodide (8 mg, 0.04 mmol) was added under nitrogen atmosphere. The mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), and the organic phases were combined and washed with saturated brine (5 mL). The mixture was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-10% gradient methanol / dichloromethane) to give a yellow solid compound, methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(diphenylmethylamino)prop-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (120 mg, 0.12 mmol, yield 62%). LCMS (ESI): [M+H] + =953.1.

[0308] Step 2: The compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(diphenylmethylamino)prop-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (120 mg, 0.12 mmol) was dissolved in ethyl acetate (6 mL). Dry palladium on carbon (containing 10% palladium and <1% water, 100 mg) was added under nitrogen. The mixture was purged with hydrogen three times. The reaction was stirred for 16 hours at 20 °C and 15 psi under hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a mixture (80 mg) of crude compound methyl 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester and methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester, which was a yellow oily liquid. LCMS(ESI):[M+H] + =776.1; 804.3.

[0309] Step 3: Compounds methyl 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester and methyl ... A mixture of oct-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid esters (80 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and lithium hydroxide (26 mg, 0.60 mmol) was added at 0 °C. The reaction mixture was stirred at 60 °C for 16 hours. The reaction solution was adjusted to pH 4 with 1M dilute hydrochloric acid and lyophilized to obtain a mixture (60 mg) of compounds 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid and 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid. LCMS (ESI): [M+H] + =762.5; 790.3.

[0310] Step 4: Add compounds 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid and 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(ethylamino) A mixture of propyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (60 mg, 0.08 mmol) and N-methylmorpholine (40 mg, 0.39 mmol) in methylpyrrolidone (2 mL) was reacted with O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (90 mg, 0.24 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), the organic phases were combined, washed with saturated brine (5 mL * 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]aceceno[3,4-g]quinazolin-10-yl)-3, A mixture (40 mg) of 8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl(1R,5S)-3-(7-ethyl-3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]acecenophenone[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which is a yellow oily liquid. LCMS(ESI): [M+H] + =744.2; 772.2.

[0311] Step 5: Add the compounds tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]acecenophenone[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester and tert-butyl(1R,5S)-3-(7-ethyl-3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy) A mixture of (40 mg, 0.05 mmol) of a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (18 mg, 0.11 mmol) in tetrahydrofuran (0.4 mL) was added to sodium tert-butoxide (10 mg, 0.10 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), the organic phases were combined, washed with saturated brine (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]aceconitin[3,4-g]quinazolin-10-yl)-3,8 A mixture (30 mg) of diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl(1R,5S)-3-(7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]acecenophenone[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which is a yellow oily liquid. LCMS(ESI): [M+H] + =804.1; 832.2.

[0312] Step 6: The compounds tert-butyl(1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]acecano[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester and tert-butyl(1R,5S)-3-(7-ethyl-3,14-difluoro-12-(( A mixture of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]acecenophenone[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid esters (30 mg, 37 μmol) was dissolved in acetonitrile (0.1 mL), and hydrogen chloride (4 M dioxane, 0.18 mL, 0.74 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to acetonitrile (500 μL). Triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain two target compounds.

[0313] Example 12: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]acecenocyclic[3,4-g]quinazolin-8-one (4.66 mg, 6 μmol, yield 16%) was a white solid, LCMS (ESI): [M+H] + =659.2; 1H NMR (400MHz, CD3OD) δppm 7.61-7.50 (m, 2H), 7.18-7.06 (m, 2H), 6.83 (d, J = 2.5Hz, 1H), 5.32-5.11 (m, 1H), 4.26-3.90 (m, 3H), 3.74 (br d,J=12.6Hz,1H),3.60-3.46(m,2H),3.39(br d,J=12.9Hz,1H),3.30-3.23(m,1H),3.19-3.05(m,4H),2.97-2.75(m,2H),2.46-2.35(m,1H), 2.31-2.02(m,3H),1.94-1.83(m,3H),1.83-1.64(m,5H),1.61-1.50(m,1H),1.31-1.15(m,1H).

[0314] Example 13: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]acecenocyclic[3,4-g]quinazolin-8-one (6.41 mg, 8 μmol, yield 23%) was a white solid, LCMS (ESI): [M+H] + =687.4; 1 H NMR (400MHz, CD3OD) δppm7.61-7.49(m,2H),7.19-7.07(m,2H),6.80(d,J=2.5Hz,1H),5.32-5.10(m,1H),4.25-4.05(m,3H),3.74(br d,J=12.5Hz,1H),3.67-3.44(m,3H),3.37(br d,J=12.9Hz,1H),3.17-3.06(m,3H),3.02-2.88(m,2H),2.87-2.72(m,2H),2.50(br t,J=11.8Hz,1H),2.31-1.66(m,12H),1.61-1.47(m,1H),1.28-1.14(m,1H),0.50(t,J=7.1Hz,3H).

[0315] Example 14: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-10-one

[0316]

[0317] Step 1: 2.00 g (3.46 mmol) of tert-butyl(1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in dioxane (20 mL) and sodium hydroxide (1.5 M aqueous solution, 18.5 mL, 27.7 mmol). Liquid bromine (0.53 mL, 10.4 mmol) was slowly added dropwise at 0 °C. The reaction was stirred at 0 °C for 3 hours, and then stirred at 20 °C for 16 hours. Add water (50 mL) to the reaction solution, adjust the pH to 4 with 2M dilute hydrochloric acid, extract with ethyl acetate (50 mL * 3), wash the organic phase with saturated brine (50 mL), dry with sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by rapid column chromatography (silica gel, 0-40% gradient ethyl acetate / petroleum ether) to give 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (1.00 g, 1.73 mmol, yield 50%). LCMS (ESI): [M + H + =581.3.

[0318] Step 2: 7-Bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (350 mg, 0.60 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)naphthyl) 402 mg (0.78 mmol) of triisopropylsilane (ethynyl) and 1.20 mL (1.81 mmol) of potassium phosphate (1.5 M aqueous solution, 1.81 mmol) were dissolved in dioxane (3.50 mL). Methanesulfonyloxy(dadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (44 mg, 0.06 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. Four identical batches of the same reaction were combined, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to give compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol, yield 30%). LCMS (ESI): [M+H] + =885.3.

[0319] Step 3: At 0°C, iodomethane (224 mg, 1.58 mmol) was added to a dimethylformamide (7 mL) suspension containing compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (650 mg, 0.72 mmol) and potassium carbonate (329 mg, 2.38 mmol). The reaction mixture was stirred at 20°C for 16 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL * 2), the organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (600 mg), which was a yellow oily liquid. LCMS (ESI): [M + H] + =899.3.

[0320] Step 4: Add cesium fluoride (1.00 g, 6.60 mmol) to a dimethylformamide (6 mL) solution of methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (600 mg, 0.66 mmol) and stir at 20 °C for 3 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phase was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to give methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester (400 mg, 0.53 mmol, yield 80%). LCMS (ESI): [M+H] + =743.6.

[0321] Step 5: The compounds methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (150 mg, 0.2 mmol), benzylprop-2-yne-1-carbamate (77 mg, 0.4 mmol), and elemental iodine (154 mg, 0.6 mmol) were dissolved in toluene (1.5 mL) and diisopropylamine (1.5 mL). Cuprous iodide (4 mg, 0.02 mmol) and dichlorobis(triphenyl) iodide were added under nitrogen atmosphere. The compound was reacted with methylphosphine (14 mg, 0.02 mmol) palladium(II) (14 mg, 0.02 mmol), stirred at 20 °C for 16 hours, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give methyl 7-(8-(5-(((benzyloxy)carbonyl)amino)pent-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester (100 mg, 0.10 mmol, yield 53%). LCMS (ESI): [M+H] + =930.6.

[0322] Step 6: The compound methyl 7-(8-(5-((((benzyloxy)carbonyl)amino)pent-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (100 mg, 0.1 mmol) was dissolved in ethyl acetate (6 mL). Dry palladium on carbon (containing 10% palladium, <1% water, 50 mg) and dry palladium hydroxide on carbon (containing 20% ​​palladium hydroxide, <1% water, 50 mg) were added under nitrogen. The mixture was purged with hydrogen three times. The reaction was stirred for 16 hours at 20 °C and 15 psi under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude compound methyl 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid ester (68 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + =804.4.

[0323] Step 7: The compound methyl 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid ester (68 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and lithium hydroxide (22 mg, 0.50 mmol) was added at 0 °C. The reaction solution was stirred at 60 °C for 16 hours. The reaction solution was adjusted to pH 4 with 1M dilute hydrochloric acid and lyophilized to obtain compound 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (45 mg, 0.05 mmol). LCMS (ESI): [M+H] + =790.4.

[0324] Step 8: Add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (65 mg, 0.17 mmol) to a solution of 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-6-carboxylic acid (45 mg, 0.05 mmol) and N-methylmorpholine (28 mg, 0.28 mmol) in methylpyrrolidone (2 mL). Stir the reaction mixture at 80 °C for 16 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), the organic phases were combined, washed with saturated brine (5 mL * 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(3,16-difluoro-18-(methoxymethoxy)-10-oxo-14-(2,2,2-trifluoroethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg), which was a yellow oily liquid. LCMS(ESI): [M+H] + =772.2.

[0325] Step 9: Add sodium tert-butoxide (10 mg, 0.10 mmol) to a solution of tert-butyl(1R,5S)-3-(3,16-difluoro-18-(methoxymethoxy)-10-oxo-14-(2,2,2-trifluoroethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg, 0.05 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (18 mg, 0.11 mmol) in tetrahydrofuran (0.4 mL). Stir the reaction mixture at 20 °C for 1 hour. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), the organic phases were combined, washed with saturated brine (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-10-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (25 mg), which is a yellow oily liquid. LCMS(ESI): [M+H] + =831.3.

[0326] Step 10: Dissolve tert-butyl(1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-10-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (25 mg, 30 μmol) in acetonitrile (0.1 mL), add hydrogen chloride (4 M dioxane, 0.15 mL, 0.6 mmol), and the reaction solution is in… The mixture was stirred at 20°C for 2 hours, concentrated under reduced pressure, and the residue was added to acetonitrile (500 μL). Triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to give a white solid compound 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-10-one (2.36 mg, 3 μmol, yield 11%). LCMS (ESI): [M+H] + =687.5; 1 H NMR (400MHz, CD3OD) δppm 7.72(s,1H),7.61-7.51(m,1H),7.25-7.01(m,3H),5.28-5.11(m,1H),4.29(br d,J=6.6Hz,1H),4.22-4.07(m,2H),3.68(br d,J=7.1Hz,1H),3.59-3.44(m,3H),3.16-2.85(m,6H),2.67(br d,J=13.1Hz,1H),2.47(br s,1H),2.30-1.99(m,4H),1.96-1.64(m,8H),1.27-1.01(m,5H).

[0327] Example 15: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-16-hydroxy-12-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-naphthyl[1',8':4,5,6]acodecin[2,3-g]quinazolin-7(8H)-one

[0328]

[0329] Step 1: At 25°C, tert-butyl(1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]acecenophenone[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (50.0 mg, 0.07 mmol) was dissolved in acetonitrile (1.00 mL) and hydrogen chloride (4 M dioxane solution, 336 μL). The reaction system was reacted at 25°C for 3 hours. The mixture was diluted with acetonitrile (3 mL), and the pH was adjusted to 8 by adding triethylamine at 0 °C. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound 10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,14-difluoro-16-hydroxy-12-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-naphthyl[1',8':4,5,6]acecanoin[2,3-g]quinazolin-7(8H)-one (8.72 mg, 14.5 μmol, yield 21%). LCMS (ESI): [M+H] + =600.4; 1 H NMR (400MHz, CD3OD) δppm 7.86 (s, 1H), 7.71 (dd, J=5.9, 9.0Hz, 1H), 7.32-7.21 (m, 2H), 6.91 (d, J=2.6Hz, 1H), 5.03 (q, J=8.8Hz, 2H), 4.72 (br d,J=13.2Hz,1H),4.48(br d,J=12.2Hz,1H),3.88(br s,1H),3.84(br s,1H),3.70(br d,J=13.2Hz,1H),2.99-2.87(m,1H),2.83-2.71(m,1H),2.47-2.34(m,1H),2.21-1.82(m,8H).

[0330] Example 16: 3,15-Difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphthol[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0331]

[0332] Step 1: Add 4A molecular sieve (60 mg) and sodium tert-butoxide (27 mg, 0.28 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (60 mg, 0.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (59 mg, 0.37 mmol) in tetrahydrofuran (600 μL). The solution was stirred at 60 °C for 16 hours. The reaction solution was diluted with water (1 mL), extracted with ethyl acetate (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy))-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (100 mg, 85.01 μmol, yield 92%). LCMS (ESI): [M+H + =706.4

[0333] Step 2: At 25°C, hydrogen chloride (4M dioxane solution, 355 μL, 1.42 mmol) was added to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy))-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (100 mg, 0.14 mmol) in acetonitrile (1000 μL). The reaction was stirred at 25°C for 1 hour. The solution was concentrated, dichloromethane (3 mL) was added, and the pH was adjusted to 8 with triethylamine. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (12.54 mg, 18.94 μmol, yield 13%). LCMS (ESI): [M+H] + =662.2; 1 H NMR (400MHz, CD3OD) δ = 7.69 (dd, J = 5.8, 8.9Hz, 1H), 7.48-7.37 (m, 1H), 7.33-7.22 ( m,2H),6.94(dd,J=2.6,5.4Hz,1H),5.52-5.29(m,1H),4.52-4.35(m,2H),4.26(br d,J=12.5Hz,1H),4.15(br dd,J=7.3,12.9Hz,1H),3.85-3.71(m,1H),3.69-3.41(m,4H),3.24-3.16(m,1H),3.01(br t,J=13.6Hz,1H),2.66-1.74(m,14H),1.66-1.52(m,2H),1.42(br d,J=7.0Hz,2H),1.32(d,J=3.5Hz,3H),1.05(br s,1H)

[0334] Examples 17A and 17B: Two stereoisomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0335]

[0336] Example 17A: Prepared using a similar synthetic route as in Example 16: The compound with a short retention time in HPLC, a yellow solid (17.47 mg). LCMS (ESI): [M+H] + =603.3; 1 H NMR (400MHz, CD3OD) δppm7.66 (dd, J=5.9, 8.8Hz, 1H), 7.36 (br s,1H),7.28(d,J=2.2Hz,1H),7.22(t,J=9.5Hz,1H),6.93(d,J=2.2Hz,1H),4.97-4.89(m,2H),4.24-4.04(m,2H),3.74(br d,J=15.0Hz,1H),3.44-3.33(m,2H),2.98(br t,J=13.3Hz,1H),2.69-2.56(m,1H),2.38(br d,J=7.7Hz,1H),2.18(br d,J=9.9Hz,1H),1.89-1.72(m,4H),1.68-1.49(m,2H),1.47-1.34(m,2H),1.30(s,3H),1.08-0.94(m,1H).

[0337] Example 17B, prepared using a similar synthetic route as in Example 16, yielded a compound with a long retention time on HPLC, appearing as a yellow solid (20.64 mg). LCMS (ESI): [M+H] + =603.1; 1 H NMR (400MHz, CD3OD) δppm7.67(dd,J=5.8,8.9Hz,1H),7.45(s,1H),7.29(d,J=2.4Hz,1H),7 .23(t,J=9.6Hz,1H),6.92(d,J=2.2Hz,1H),4.98-4.90(m,2H),4.27-4.06(m,2H),3.77(br d,J=15.4Hz,1H),3.35(br d,J=13.4Hz,2H),2.98(br t,J=13.4Hz,1H),2.62(br s,1H),2.37(br s,1H),2.16(br d,J=10.6Hz,1H),1.91-1.72(m,4H),1.58(br s,2H),1.39(br s,2H),1.29(s,3H),1.01(br d,J=6.6Hz,1H).

[0338] Examples 18A and 18B: Two isomers of (R)-13-((2-oxabicyclo[2.2.2]oct-1-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0339]

[0340] Example 18A: Prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =645.3; 1 H NMR (400MHz, CD3OD) δppm 7.70-7.63(m,1H),7.35-7.20(m,3H),6.88(br d,J=4.0Hz,1H),4.24-4.08(m,3H),4.06-3.88(m,3H),3.72(br d,J=14.8Hz,1H),3.45-3.34(m,2H),2.96(br t,J=13.0Hz,1H),2.71-2.57(m,1H),2.37(br s,1H),2.16(br d,J=10.3Hz,1H),2.07-1.95(m,2H),1.91-1.69(m,11H),1.65-1.34(m,4H),1.31(s,3H),1.01(br d,J=7.9Hz,1H).

[0341] Example 18B was prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =645.3; 1H NMR (400MHz, CD3OD) δppm 7.73-7.62(m,1H),7.41(s,1H),7.32-7.16(m,2H),6.92(d,J=2.1Hz,1H),4.24-4.11(m,3H),4.06(br d,J=13.0Hz,1H),3.97-3.88(m,2H),3.75(br d,J=14.9Hz,1H),3.35(br s,2H),2.96(br t,J=13.4Hz,1H),2.64(br d,J=12.2Hz,1H),2.37(br s,1H),2.14(br d,J=9.0Hz,1H),2.00(br s,2H),1.91-1.72(m,11H),1.57(br s,4H),1.29(s,3H),0.99(br s,1H).

[0342] Example 19: (R)-13-((2-oxabicyclo[2.2.2]oct-4-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0343]

[0344] Example 19: LCMS(ESI):[M+H) was prepared using a similar synthetic route as in Example 16. + =645.3; 1H NMR (400MHz, CD3OD) δppm 7.68(dd,J=5.9,8.9Hz,1H),7.47-7.33(m,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9.5Hz,1H),6.99-6.88(m,1H),4.18(br d,J=12.8Hz,1H),4.13-3.98(m,3H),3.87(s,2H),3.82-3.68(m,2H),3.44-3.37(m,1H),2.98(br t,J=13.1Hz,1H),2.72-2.57(m,1H),2.38(br s,1H),2.18(br d,J=9.8Hz,1H),2.10-1.97(m,2H),1.87-1.65(m,11H),1.64-1.52(m,2H),1.41(br d,J=4.8Hz,2H),1.32(d,J=5.3Hz,3H),1.01(br d,J=6.7Hz,1H).

[0345] Examples 20A and 20B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((4-methoxybicyclo[2.2.2]oct-1-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0346]

[0347] Example 20A: Prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =673.5; 1H NMR (400MHz, CD3OD) δppm 7.71-7.60(m,1H),7.36-7.31(m,1H),7.31-7.27(m,1H),7.27-7.19(m,1H),6.95-6.86(m,1H),4.19(br s,3H),3.73-3.69(m,1H),3.43-3.36(m,1H),3.17(d,J=3.7Hz,3H),3.04-2.90(m,1H),2.72-2.56(m,1H),2.45-2.28(m,1H),2.16(br d,J=12.6Hz,2H),1.82-1.63(m,15H),1.63-1.54(m,4H),1.51-1.35(m,2H),1.31(s,3H),1.12-0.85(m,1H).

[0348] Example 20B was prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =673.4; 1 H NMR(400MHz,CD3OD)δppm 7.74-7.64(m,1H),7.47-7.40(m,1H),7.32-7.28(m,1H),7.28-7.21(m,1H),6.94(d,J= 2.6Hz,1H),4.59-4.51(m,1H),4.19-4.06(m,3H),3.85-3.67(m,1H),3.41-3.34(m,1H) ,3.21-3.17(m,3H),3.08-2.88(m,1H),2.73-2.60(m,1H),2.46-2.32(m,1H),2.21-2.0 3(m,1H),1.91-1.58(m,19H),1.49-1.34(m,2H),1.34-1.26(m,3H),1.13-0.90(m,1H).

[0349] Examples 21A and 21B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0350]

[0351] Example 21A: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =644.3; 1 H NMR(400MHz,CD3OD)δppm 8.55(s,1H),7.68(dd,J=5.7,9.0Hz,1H),7.38(s,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9. 5Hz,1H),6.93(d,J=2.6Hz,1H),4.50(d,J=4.6Hz,2H),4.27(td,J=4.7,9.1Hz,1H),4.15(br d,J=13.4Hz,1H),3.82-3.70(m,1H),3.53-3.33(m,5H),3.16-2.94(m,3H),2.69-2.55(m,1H),2.45-2.33(m,1H) ),2.27-2.08(m,5H),2.04-1.93(m,4H),1.88-1.73(m,4H),1.64-1.50(m,2H),1.45-1.35(m,2H),1.31(s,3H).

[0352] Example 21B was prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =644.2; 1 H NMR(400MHz,CD3OD)δppm 8.55(br s,1H),7.73-7.65(m,1H),7.46(s,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9 .7Hz,1H),6.92(d,J=2.6Hz,1H),4.50(s,2H),4.34-4.23(m,1H),4.16(br d,J=13.0Hz,1H),3.77(br d,J=15.2Hz,1H),3.58-3.33(m,5H),3.11(br dd,J=5.6,11.6Hz,2H),3.00(br t,J=13.0Hz,1H),2.69-2.56(m,1H),2.44-2.31(m,1H),2.30-2.10(m,5H),2.05-1 .97(m,4H),1.88-1.74(m,4H),1.64-1.51(m,2H),1.48-1.36(m,2H),1.30(s,3H).

[0353] Examples 22A and 22B: Two stereoisomers of 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0354]

[0355] Step 1: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150.00 mg, 0.23 mmol) in N,N-dimethylformamide (1.50 mL), cesium carbonate (83.14 mg, 0.26 mmol) and methyl iodoformane (0.03 mL, 0.47 mmol) were added. The mixture was stirred for 16 hours under nitrogen protection and at 25 °C. Dilute with water (3 mL), extract with ethyl acetate (5 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to give the crude compound (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg). LCMS (ESI): [M+H + =661.2.

[0356] Step 2: Add 4A molecular sieve (150 mg) and sodium tert-butoxide (41.6 mg, 0.42 mmol) to a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (140 mg, 0.21 mmol) and (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (129.87 mg, 0.85 mmol) in tetrahydrofuran (1.50 mL). The solution was stirred at 60°C for 4 hours. The reaction solution was diluted with water (2 mL), extracted with ethyl acetate (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow crude compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg). LCMS(ESI): [M+H] + =714.4

[0357] Step 3: At 25°C, add hydrogen chloride (4M dioxane solution, 1.05 mL, 4.20 mmol) to a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg, 0.21 mmol) in acetonitrile (1.5 mL), and stir the reaction at 25°C for 1 hour. Concentrate the solution, add acetonitrile (3 mL), and adjust the pH to 8 with triethylamine. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give two stereoisomers of the compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol.

[0358] Example 22A: LCMS(ESI): [M+H] + =670.3; 1H NMR(400MHz,CD3OD)δppm 7.83-7.72(m,1H),7.63(dd,J=6.0,9.0Hz,1H),7.28-7.15(m,2H),6.88(d,J=2.5Hz,1H),5.00(brs,2H),4.31-4.25(m,2H),4.13(br d,J=13.1Hz,1H),3.79(br d,J=14.4Hz,1H),3.44-3.33(m,3H),3.29-3.17(m,2H),2.93-2.79(m,2H),2.78 -2.75(m,3H),2.64-2.44(m,3H),2.25-2.10(m,2H),2.09-1.58(m,8H),1.55(br s,1H),1.43-1.19(m,8H).

[0359] Example 22B: LCMS(ESI): [M+H] + =670.4; 1 H NMR (400MHz, CD3OD) δppm 7.80 (s, 1H), 7.63 (dd, J=5.9, 9.0Hz, 1H), 7.27-7.13 (m, 2H), 6.88 (d, J=2.5Hz, 1H), 5.00 (br s, 2H), 4.28 (br d,J=7.0Hz,2H),4.09(brd,J=13.1Hz,1H),3.79(br d,J=14.3Hz,1H),3.47-3.32(m,3H),3.28-3.10(m,2H),2.89-2.78(m,2H),2.75(s,3H),2.6 3-2.45(m,3H),2.23-2.09(m,2H),2.07-1.61(m,8H),1.59-1.50(m,1H),1.44-1.21(m,8H).

[0360] Example 23: 13-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0361]

[0362] Example 23: LCMS (ESI): [M+H) was prepared using a similar synthetic route as in Example 16. +=670.3; 1 H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.69 (br dd, J = 5.8, 8.9Hz, 1H), 7.51-7.36 (m, 1H), 7.31 (br d, J = 2.3Hz, 1H), 7.26 (br t, J = 9.5Hz, 1H), 6.95 (br s,1H),4.61(br s,2H),4.35-4.14(m,2H),3.77(br d,J=14.5Hz,1H),3.55(br s,1H),3.48-3.25(m,3H),3.28(br s,1H),3.18-2.94(m,2H),2.64(br s,1H),2.47-2.02(m,8H),1.94-1.70(m,4H),1.59(br d,J=8.2Hz,2H),1.42(br s,2H),1.32(br d,J=2.7Hz,3H),1.07(br s,1H),0.89-0.54(m,4H).

[0363] Examples 24A and 24B: Two isomers of 13-((1s,7a's)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0364]

[0365] Example 24A: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =706.5; 1H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.9,8.9Hz,1H),7.33(s,1H),7.30-7.27(m,1H),7.23(t,J=9.6H z,1H),6.93(d,J=2.5Hz,1H),4.74-4.50(m,1H),4.41-4.24(m,2H),4.18(br d,J=12.5Hz,1H),4.10-3.98(m,1H),3.72(br d,J=14.6Hz,1H),3.49-3.32(m,3H),3.25-3.15(m,1H),3.02-2.83(m,2H),2.78-2.57(m,2H),2.38(br d,J=6.5Hz,1H),2.29(br dd,J=6.1,13.6Hz,1H),2.22-2.11(m,2H),2.03(s,1H),1.97-1.91(m,1H),1.87 -1.73(m,5H),1.64-1.50(m,2H),1.49-1.33(m,4H),1.32-1.27(m,3H),1.00(br d,J=7.3Hz,1H).

[0366] Example 24B was prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =706.8; 1H NMR (400MHz, CD3OD) δppm 7.69(dd,J=5.8,9.1Hz,1H),7.43(s,1H),7.31(d,J=2.6Hz,1H),7.25(t,J=9.6Hz,1H),6.94(d,J=2.6Hz,1H),4.63(br s,1H),4.41-4.28(m,2H),4.20(br d,J=12.5Hz,1H),4.10(br d,J=13.3Hz,1H),3.77(br d,J=14.9Hz,1H),3.41-3.34(m,2H),3.30(br s,1H),3.24-3.14(m,1H),2.99(br t,J=13.2Hz,1H),2.89(brd,J=12.0Hz,1H),2.78-2.59(m,2H),2.44-2.25(m,2H),2.23-2.10(m,2H),2.04(br d,J=13.5Hz,1H),1.98-1.92(m,1H),1.89-1.75(m,5H),1.60(br d,J=8.4Hz,2H),1.52-1.36(m,4H),1.31(s,3H),1.02(br s,1H).

[0367] Example 25: 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0368]

[0369] Example 25 describes the preparation of LCMS (ESI): [M+H] using a similar synthetic route as in Example 16. + =656.1; 1H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.70 (dd, J=5.9, 8.8Hz, 1H), 7.49-7.30 (m, 2H), 7.26 (t, J=9.5Hz, 1H), 6.95 (br s, 1H), 5.19 (br d,J=6.2Hz,2H),4.70-4.47(m,2H),4.29(br d,J=13.0Hz,1H),4.16(br d,J=13.4Hz,2H),3.83-3.68(m,2H),3.56(br s,1H),3.46-3.34(m,2H),3.16-2.91(m,3H),2.78-2.59(m,2H),2.48-2.26(m,2H),2.25- 1.98(m,4H),1.91-1.71(m,4H),1.67-1.38(m,4H),1.32(d,J=3.1Hz,3H),1.06(brs,1H).

[0370] Example 26: (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0371]

[0372] Example 26: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =674.3; 1 H NMR(400MHz,CD3OD)δppm 7.69(dd,J=8.9,5.9Hz,1H),7.43(s,1H),7.33-7.21(m,2H),6.97-6.92(m,1H),4. 44-4.34(m,2H),4.22-4.00(m,2H),3.79-3.64(m,5H),3.46-3.35(m,2H),2.98(br t,J=13.0Hz,1H),2.80-2.57(m,7H),2.38(br s,1H),2.17(br s,1H),1.91-1.74(m,4H),1.72-1.24(m,8H),1.00(br s,1H),0.82-0.70(m,2H),0.56(s,2H).

[0373] Example 27: (R)-13-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0374]

[0375] Example 27: LCMS(ESI):[M+H) prepared using a similar synthetic route as in Example 16. + =632.3; 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.70(dd,J=5.9,9.0Hz,1H),7.50-7.38(m,1H),7.32(d,J=2.6Hz,1H),7.26(t,J=9.6Hz,1H),6.98-6.88(m,1H),4.64(br s,2H),4.43-4.29(m,2H),4.25(br d,J=13.2Hz,1H),4.18-4.05(m,1H),3.75(br d,J=14.7Hz,1H),3.44-3.37(m,1H),3.00(br s,2H),2.72(br s,6H),2.38(br s,1H),2.19(brs,1H),1.92-1.74(m,4H),1.60(br s,2H),1.50-1.34(m,3H),1.32(d,J=4.2Hz,3H),1.02(br s,1H),0.88(s,2H),0.73(br s,2H).

[0376] Examples 28A and 28B: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-(((S)-1-methylpyrrolidine-2-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0377]

[0378] Example 28A, prepared using a similar synthetic route as in Example 16, shows a short retention time peak on HPLC, 0.94 mg, and is a yellow solid. LCMS (ESI): [M+H] + =618.2; 1H NMR (400MHz, CD3OD) δppm 7.67 (dd, J=8.9, 5.7Hz, 1H), 7.39-7.17 (m, 3H), 6.93 (d, J=2.4Hz, 1H), 4.65-4.44 (m, 3H), 4.27-4.01 (m, 2H), 3.73 (br d,J=15.2Hz,1H),3.41(br d,J=13.0Hz,1H),2.98(br t,J=13.3Hz,1H),2.74-2.59(m,5H),2.46-2.08(m,3H),2.04-1.70(m,8H),1.65-1.24(m,8H),1.02(br s,1H).

[0379] Example 28B, prepared using a similar synthetic route as in Example 16, shows a peak with a relatively long retention time on HPLC, 1.04 mg, and is a yellow solid. LCMS (ESI): [M+H] + =618.2; 1 H NMR (400MHz, CD3OD) δppm 7.74-7.61(m,1H),7.48-7.37(m,1H),7.33-7.18(m,2H),6.92(br s,1H),4.65-4.38(m,3H),4.35-4.04(m,2H),3.82-3.65(m,1H),3.42-3.38(m,2H),3.05-2.90(m,1H),2.78(s,3H),2.61(br s,2H),2.43-2.06(m,3H),2.05-1.69(m,7H),1.67-1.16(m,8H),1.02(br s,1H).

[0380] Examples 29 and 30: 13-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazole 17-Linol and 3,15-difluoro-13-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolinol-17-Linol

[0381]

[0382] Example 29, prepared using a similar synthetic route as in Example 16, yielded (1.5 mg, 2.17 μmol, 1% yield) a yellow solid. LCMS (ESI): [M+H] + =692.4; 1 H NMR(400MHz,CD3OD)δppm 7.69(br dd,J=5.8,9.0Hz,1H),7.45(s,1H),7.34-7.20(m,2H),6.94(d,J=2.5Hz,1H),4.50-4.29(m,2H),4.26-4.09(m,2H),4.02-3.59(m,4H),3.38(br s,1H),3.07-2.84(m,3H),2.71-2.56(m,2H),2.39(br s,1H),2.26-1.94(m,5H),1.91-1.73(m,5H),1.60(br s,2H),1.41(br s,2H),1.31(s,3H),1.02(br s,1H).

[0383] Example 30, prepared using a similar synthetic route as in Example 16, yielded (8.0 mg, 11.89 μmol, 7% yield) a yellow solid. LCMS (ESI): [M+H] + =674.4; 1 H NMR(400MHz,CD3OD)δppm 7.74-7.65(m,1H),7.47-7.18(m,3H),6.95(br s,1H),6.93-6.53(m,1H),4.53-4.00(m,4H),3.96-3.53(m,2H),3.48-3.36(m,2H),3.32-3.1 7(m,1H),3.05-2.52(m,5H),2.45-1.91(m,6H),1.90-1.72(m,4H),1.64-1.36(m,5H),1.32(br d,J=3.7Hz,3H),1.03(br s,1H).

[0384] Example 31: (R)-13-((2,6-dimethylene-tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0385]

[0386] Example 31: LCMS (ESI): [M+H) was prepared using a similar synthetic route as in Example 16. + =668.3; 1 H NMR (400MHz, CD3OD) δppm 7.59 (dd, J=5.9, 9.1Hz, 2H), 7.22 (d, J=2.6Hz, 1H), 7.18-7.12 (m, 1H), 6.84 (d, J=2.6Hz, 1H), 5.22 (br s, 4H), 4.61 (br d,J=13.8Hz,1H),4.37(br d,J=14.8Hz,2H),3.86(br d,J=15.5Hz,2H),3.69(br d,J=14.9Hz,1H),3.52(br d,J=13.5Hz,1H),3.08-2.95(m,3H),2.84-2.73(m,2H),2.61-2.51(m,1H), 2.27-2.05(m,3H),1.85-1.64(m,4H),1.54-1.34(m,3H),1.32-1.03(m,8H).

[0387] Example 32: (Z)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0388]

[0389] Example 32: LCMS (ESI): [M+H) was prepared using a similar synthetic route as in Example 16. + =654.5; 1 H NMR (400MHz, CD3OD) δppm 7.81(dd,J=5.7,9.0Hz,1H),7.38-7.27(m,2H),7.09-6.98(m,1H),6.88(br d,J=8.7Hz,1H),5.69-5.59(m,1H),5.14(br s,3H),4.78-4.37(m,2H),4.32-3.95(m,3H),3.69-3.52(m,2H),3.51-3.36(m,2H),3.05-2.53(m,4H),2.40-1.69(m,12H),1.61(br s,1H),1.32(d,J=3.8Hz,3H).

[0390] Examples 33A and 33B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((1-morpholinocyclopropyl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0391]

[0392] Example 33A: LCMS (ESI): [M+H] prepared using a similar synthetic route as in Example 16. + =660.3; 1 H NMR (400MHz, CD3OD) δppm 7.67 (dd, J=6.2, 8.6Hz, 1H), 7.41-7.09 (m, 3H), 6.93 (s, 1H), 4.51 (br d, J=3.0Hz, 3H), 4.17-4.10 (m, 1H), 4.02 (br d,J=12.5Hz,1H),3.72(brd,J=13.9Hz,1H),3.59(br d,J=3.9Hz,4H),3.40(br d,J=13.4Hz,2H),2.88(br d,J=4.3Hz,4H),2.67-2.62(m,1H),2.43-2.33(m,1H),2.23-2.13(m,1H),1.87-1.68( m,4H),1.64-1.50(m,2H),1.45-1.35(m,2H),1.31(s,3H),1.05-0.95(m,1H),0.75(br d,J=9.9Hz,4H).

[0393] Example 33B was prepared using a similar synthetic route as in Example 16: LCMS(ESI):[M+H] + =660.2; 1H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.7,8.9Hz,1H),7.42(s,1H),7.31-7.19(m,2H),6.92(d,J=2.1Hz,1H),4.51(d,J=6.8Hz,3H),4.18-4.04(m,2H),3.75(br d,J=14.0Hz,1H),3.63-3.55(m,4H),3.36(br s,2H),2.91-2.83(m,4H),2.68-2.62(m,1H),2.42-2.30(m,1H),2.20-2.10(m,1H),1.88-1.71(m,4H),1.64-1.53(m,2H),1.39(br d,J=6.9Hz,2H),1.30(s,3H),1.04-0.94(m,1H),0.76(br d,J=10.0Hz,4H).

[0394] Example 34: 13-(((S)-4,4-difluoro-1-methylpyrrolidone-2-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0395]

[0396] Example 34 was prepared using a similar synthetic route as in Example 16: 1 H NMR (400MHz, CD3OD) δppm 7.69 (dd, J=6.1, 8.8Hz, 1H), 7.49-7.17 (m, 3H), 6.94 (br s, 1H), 4.63 (br s,2H),4.57-4.44(m,2H),4.23-4.03(m,2H),3.84-3.70(m,1H),3.47-3.36(m,2H),3.12-2 .94(m,2H),2.82-2.62(m,2H),2.50(s,3H),2.44-2.15(m,3H),1.94-1.71(m,4H),1.60(br s,2H),1.40(br s,2H),1.32(d,J=4.4Hz,3H),1.02(br s,1H).

[0397] Example 35: 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0398]

[0399] Example 35 describes the preparation of LCMS (ESI): [M+H] using a similar synthetic route as in Example 16. + =632.4; 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.69(dd,J=8.9,5.9Hz,1H),7.45-7.36(m,1H),7.31(d,J=2.6Hz,1H),7 .25(t,J=9.5Hz,1H),6.99-6.87(m,1H),5.35-5.27(m,1H),4.29-4.02(m,3H),3 .82-3.72(m,1H),3.48-3.37(m,3H),3.07-2.96(m,1H),2.92-2.78(m,5H),2.72 -2.60(m,1H),2.44-2.11(m,4H),2.07-1.96(m,2H),1.91-1.74(m,6H),1.59(br d,J=6.5Hz,2H),1.45(br d,J=6.1Hz,3H),1.32(d,J=3.4Hz,3H).

[0400] Example 36: 13-(2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0401]

[0402] Example 36: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =680.3; 1H NMR (400MHz, CD3OD) δppm 7.69 (dd, J=8.7, 5.9Hz, 1H), 7.44-7.34 (m, 1H), 7.32-7.21 (m, 2H), 6.95 (br s,1H),4.29-4.16(m,3H),4.13-4.03(m,1H),3.81-3.71(m,1H),3.54-3.37(m,3H),3 .22-3.09(m,2H),3.04-2.84(m,2H),2.72-2.59(m,2H),2.46-1.70(m,12H),1.59(br s,2H),1.40(br d,J=5.5Hz,2H),1.32(br d, J = 4.6 Hz, 3H).

[0403] Example 37: 3,15-Difluoro-13-((hexahydrocyclopropano[b]pyrrolizin-5a(3H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0404]

[0405] Example 37: LCMS(ESI):[M+H) was prepared using a similar synthetic route as in Example 16. + =656.1; 1 H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.9,8.9Hz,1H),7.45-7.31(m,1H),7.30-7.18(m,2H),7.02-6. 84(m,1H),4.32-3.94(m,5H),3.77-3.69(m,1H),3.44-3.34(m,2H),3.17(br s,4H),2.67-2.58(m,1H),2.42-2.34(m,1H),2.26-2.10(m,4H),1.98(br d,J=4.4Hz,3H),1.81-1.69(m,4H),1.62-1.51(m,2H),1.44-1.34(m,2H),1.29(d,J=4.0Hz,3H),1.07-0.92(m,1H),0.88-0.55(m,2H).

[0406] Example 38: 13-((2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0407]

[0408] Example 38: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =692.7; 1 H NMR (400MHz, CD3OD) δppm 7.61-7.53(m,1H),7.28-7.07(m,3H),6.83(d,J=2.6Hz,1H),4.92(br d,J=3.8Hz,2H),4.23-4.06(m,3H),3.97(br d,J=13.1Hz,1H),3.65(br t,J=14.6Hz,2H),3.41-3.32(m,2H),3.30-3.24(m,1H),3.10-2.98(m,1H),2.93-2.81(m,1H),2.75-2.67(m,1H),2.60-2.46( m,3H),2.31(q,J=14.4Hz,2H),2.14-2.00(m,1H),1.80-1.60(m,4H),1.55-1.38(m,2H),1.35-1.16(m,6H),0.95-0.84(m,1H).

[0409] Example 39: (R)-13-(3-(dimethylamino)azacyclobutyl)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0410]

[0411] Example 39: LCMS (ESI): [M+H) prepared using a similar synthetic route as in Example 16. + =603.1. 1H NMR (400MHz, CD3OD) δppm 7.73-7.63(m,1H),7.41-7.14(m,3H),6.92(dd,J=2.8,4.7Hz,1H),4.22(br s,2H),4.13-3.85(m,4H),3.69(br s,1H),3.37(br s,2H),3.29-3.25(m,1H),2.93(s,1H),2.67(br d,J=4.5Hz,1H),2.44-2.34(m,1H),2.26(s,6H),2.15-2.04(m,1H),1.87-1.68(m,4H),1.56(br s,2H),1.36(br s,2H),1.30(d,J=5.4Hz,3H),1.01-0.87(m,1H).

[0412] Example 40: (3R)-1-(17-amino-3,15-difluoro-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0413]

[0414] Step 1: At 0°C, add hydrogen chloride (4M dioxane solution, 5.68 mL, 22.71 mmol) to an acetonitrile solution (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.00 g, 1.51 mmol). Stir the solution at 20°C for 1 hour. Concentration under reduced pressure yielded the crude compound (R)-3,15-difluoro-17-hydroxy-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.00 g), a brown solid. LCMS (ESI): [M+H] + =617.1.

[0415] Step 2: At 0°C, triethylamine (1.04 mL, 7.46 mmol) was added to a solution of compound (R)-3,15-difluoro-17-hydroxy-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (crude, 920 mg, 1.49 mmol) in dichloromethane (20.0 mL). Triethylamine was added dropwise at 0°C (276 μL, 1.64 mmol), and the solution was stirred at 0°C for 4 hours. After the reaction was complete, the solution was quenched with ice water (10 mL), extracted with dichloromethane (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yltrifluoromethanesulfonate (510 mg, 0.68 mmol, yield 46%). LCMS (ESI): [M+H + =749.1.

[0416] Step 3: Under a nitrogen atmosphere, add tert-butyl carbamate (110 mg, 0.94 mmol), cesium carbonate (653 mg, 2.00 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (38.6 mg, 0.07 mmol), and tris(dibenzylacetone)dipalladium (61.2 mg, 0.07 mmol) to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yltrifluoromethanesulfonate (500 mg, 0.67 mmol) in tetrahydrofuran (5.00 mL), to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yltrifluoromethanesulfonate (500 mg, 0.67 mmol), to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl) ... The mixture was stirred at 70°C for 2 hours. After cooling naturally to room temperature, water (2 mL) was added, and extraction was performed with ethyl acetate (2 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-60% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl) tert-butyl carbamate (110 mg, 0.15 mmol, yield 23%). LCMS (ESI): [M+H] + =716.5.

[0417] Step 4: Compound (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl) tert-butyl carbamate (110 mg, 0.15 mmol) and phenylsilane (166 mg, 1.54 mmol) were dissolved in tetrahydrofuran (5.0 mL), and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (10.3 mg, 15.37 μmol) was added. The reaction was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid compound (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl) tert-butyl carbamate (53.0 mg, 75.51 μmol, yield 49%). LCMS (ESI): [M+H + =702.1.

[0418] Step 5: Dissolve (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl) tert-butyl carbamate (50.0 mg, 71.25 μmol), 4A molecular sieve (20.0 mg), and sodium tert-butoxide (34.2 mg, 0.36 mmol) in tetrahydrofuran (500 μL), add (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (54.0 mg, 0.36 mmol), and stir the reaction at 60 °C for 16 hours. The mixture was diluted with water (300 μL) and extracted with ethyl acetate (300 μL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound, tert-butyl(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (28.0 mg, 37.05 μmol, yield 52%). LCMS (ESI): [M+H]+ =755.4.

[0419] Step 6: Dissolve tert-butyl(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (30.0 mg, 39.74 μmol) in trifluoroacetic acid / dichloromethane (volume ratio 1:4, 300 μL) and stir at 25 °C for 2 hours. The reaction solution was concentrated under vacuum. The residue was added to dichloromethane (300 μL) and neutralized with triethylamine (until pH > 7). The solvent was removed by concentration under reduced pressure. The residue was purified by preparative HPLC to give a yellow solid compound (3R)-1-(17-amino-3,15-difluoro-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (1.09 mg, 1.59 μmol, yield 4%). LCMS (ESI): [M+H] + =655.3; 1 HNMR (400MHz, CD3OD) δppm 7.60 (dd, J=6.3, 8.7Hz, 1H), 7.52-7.41 (m, 1H), 7.37-7.33 (m, 1H), 7.19 (br s, 1H), 6.86 (s, 1H), 5.04 (br s,2H),4.41-4.26(m,2H),4.25-4.15(m,1H),4.14-4.04(m,1H),3.89- 3.82(m,1H),3.80-3.70(m,1H),3.48-3.38(m,2H),3.07-2.92(m,1H), 2.88-2.79(m,2H),2.69-2.48(m,2H),2.42-2.28(m,1H),2.24-2.16(m ,3H),2.09-1.96(m,3H),1.92-1.74(m,6H),1.67-1.51(m,4H),1.35(br s,3H).

[0420] Example 41: 3,15-Difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteratedmethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one

[0421]

[0422] Step 1: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (100 mg, 0.15 mmol) and cesium carbonate (54.3 mg, 0.17 mmol) in N,N-dimethylformamide (2.0 mL), deuterated iodomethane (19 μL, 0.30 mmol) was added. The solution was stirred at 25 °C for 16 hours. Water (6 mL) was added, and the mixture was extracted with ethyl acetate (6 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. A brown, oily crude compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteratedmethyl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (120 mg) was obtained. LCMS (ESI): [M+H] + =678.1.

[0423] Step 2: Add sodium tert-butoxide (32.6 mg, 0.34 mmol) to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteratedmethyl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (115 mg, 0.17 mmol), 4A molecular sieve (115 mg), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (81 mg, 0.51 mmol) in tetrahydrofuran (2.0 mL). Stir the mixture at 60 °C for 16 hours. Dilute with water (2 mL), extract with ethyl acetate (3 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to give a yellow oily crude compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteratedmethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (200 mg). LCMS(ESI): [M+H] + =737.5.

[0424] Step 3: To a solution of 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuterated methyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (200 mg, 0.27 mmol) in acetonitrile (4.0 mL), hydrogen chloride (4 M dioxane solution, 1018 μL, 4.07 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was dried under nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteratedmethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (17.49 mg, 0.03 mmol, 9% yield). LCMS (ESI): [M+H] +=693.3. 1 HNMR(400MHz,CD3OD)δppm 8.11(d,J=9.8Hz,1H),7.70(dd,J=5.9,8.9Hz,1H),7.37-7.23(m,2H),7.10-6.98(m,1H),5.47-5.30(m,1H),4.49-4 .39(m,2H),4.38-4.30(m,1H),4.23-4.13(m,1H),3.60-3.49(m,2H),3.48-3.36(m,4H),3.21-3.10(m,1H),2.76(br d,J=4.5Hz,1H),2.66-2.55(m,1H),2.48(br dd,J=6.7,13.6Hz,1H),2.39-2.31(m,1H),2.24-2.08(m,5H),2.01-1.92(m,1H),1.85(br s,1H),1.82-1.73(m,2H),1.53(br d,J=6.6Hz,2H),1.41-1.33(m,1H),1.31-1.25(m,3H),1.15(br s,1H).

[0425] Example 42: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol

[0426]

[0427] Step 1: Add sodium tert-butoxide (9.0 mg, 0.09 mmol) to a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol and (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (20.0 mg, 0.03 mmol) in tetrahydrofuran (0.4 mL). Stir the mixture at 60 °C for 16 hours under nitrogen protection. Dilute with water (2 mL) at 0 °C, extract with ethyl acetate (2 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified using a preparative thin-layer chromatography plate (silica gel, dichloromethane:methanol = 10:1) to give a yellow solid compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (10 mg, 0.01 mmol, yield 46%). LCMS (ESI): [M+H] + =702.4.

[0428] Step 2: Add hydrogen chloride (4M dioxane solution, 53 μL, 0.21 mmol) to a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (10 mg, 0.01 mmol) in acetonitrile (200 μL). Incubate the solution at 25 °C. Stir for 1 hour. The solution was dried under nitrogen, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol (2.22 mg, 3.38 μmol, yield 24%). LCMS (ESI): [M+H] + =658.4; 1H NMR (400MHz, CD3OD) δppm 7.77(br s,1H),7.62-7.50(m,1H),7.40-7.25(m,2H),6.97(br s,1H),5.13(br s,2H),4.53-4.40(m,2H),4.29(br d,J=12.5Hz,1H),4.22-3.99(m,2H),3.85(br d,J=8.2Hz,1H),3.69-3.53(m,4H),3.49-3.36(m,3H),3.17-2.92(m,2H),2 .72-2.57(m,3H),2.34-1.93(m,5H),1.92-1.71(m,3H),1.40-1.25(m,5H).

[0429] Examples 42A to 42D: Four isomers of 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-(((S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0430] 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol was separated by SFC (column: DAICELCHIRALPAK IG (250mm*30mm,10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia / ethanol; phase B was maintained at 60%; flow rate: 80 mL / min) to obtain its four corresponding isomers.

[0431] Example 42A: LCMS(ESI): [M+H] + =658.3; SFC analysis (column: Chiralpak IG-3 50×4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position is 0.846 min; 1H NMR (400MHz, CD3OD) δppm 7.77-7.73 (dd, J=6.0, 9.0Hz, 1H), 7.52 (s, 1H), 7.34-7.24 (m, 2H), 6.95 (d, J=2.6Hz, 1H), 5.14 (br s,2H),4.50-4.40(m,2H),4.28(br d,J=14.1Hz,1H),4.13-4.02(m,2H),3.85-3.82(m,1H),3.65-3.57(m,4H),3.45-3.33(m,3H),3.28-3.22(m,1H), 3.19-3.06(m,1H),3.02-2.88(m,2H),2.70-2.58(m,3H),2.29-1.96(m,5H),1.88-1.71(m,3H),1.31-1.26(m,3H).

[0432] Example 42B: LCMS(ESI): [M+H] + =658.3; SFC analysis (column: Chiralpak IG-3 50×4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position is 2.271 min; 1 H NMR (400MHz, CD3OD) δppm 7.77-7.70 (dd, J=6.0, 9.0Hz, 1H), 7.49 (s, 1H), 7.34-7.24 (m, 2H), 6.95 (d, J=2.6Hz, 1H), 5.14 (br s,2H),4.59-4.40(m,2H),4.26(br d,J=14.1Hz,1H),4.17-4.14(m,1H),4.08-4.05(m,1H),3.91-3.78(m,1H),3.66-3.52(m,4H),3.50-3.3 0(m,4H),3.25-2.88(m,3H),2.65-2.58(m,3H),2.29-1.96(m,5H),1.88-1.71(m,3H),1.31-1.26(m,3H).

[0433] Example 42C: LCMS(ESI): [M+H] +=658.3; SFC analysis (column: Chiralpak IG-3 50×4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position is 0.893 min; 1 H NMR (400MHz, CD3OD) δppm 7.76 (dd, J=6.2, 9.0Hz, 1H), 7.53 (s, 1H), 7.38-7.26 (m, 2H), 6.95 (d, J=2.4Hz, 1H), 5.12 (br s,2H),4.51-4.31(m,2H),4.31-4.19(m,1H),4.18-4.07(m,1H),3.97(m,1H),3.84(m,1H),3.65-3.49( m,4H),3.48-3.30(m,4H),3.18-2.78(m,3H),2.72-2.51(m,3H),2.25-1.69(m,8H),1.32-1.23(m,3H).

[0434] Example 42D: LCMS(ESI): [M+H] + =658.3; SFC analysis (column: Chiralpak IG-3 50×4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position is 3.209 min; 1 H NMR (400MHz, CD3OD) δppm 7.74 (dd, J=6.2, 9.0Hz, 1H), 7.57-7.53 (m, 1H), 7.38-7.27 (m, 2H), 6.95 (m, 1H), 5.16 (br s,2H),4.55-4.45(m,2H),4.35-4.24(m,1H),4.18-4.06(m,2H),3.92-3.81(m,1H),3.65-3.52(m,5 H),3.44-3.30(m,3H),3.16-2.88(m,3H),2.72-2.57(m,3H),2.32-1.75(m,8H),1.32-1.23(m,3H).

[0435] Examples 43A and 43B: Two stereoisomers of 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0436]

[0437] Example 43A: LCMS(ESI):[M+H] was prepared using a similar synthetic route as in Example 42. + =664.2; 1 H NMR(400MHz,CD3OD)δppm 7.74(dd,J=5.9,9.1Hz,1H),7.51(s,1H),7.35-7.22(m,2H),6.94(d,J=2. 6Hz,1H),5.41-5.18(m,1H),4.31-4.25(m,1H),4.24-4.14(m,2H),4.09(br d,J=13.1Hz,1H),3.83(td,J=6.3,12.5Hz,1H),3.64-3.51(m,3H),3.42(br d,J=12.8Hz,1H),3.34(br s,1H),3.30-2.93(m,6H),2.63(br d,J=3.0Hz,2H),2.39-2.09(m,4H),2.04-1.71(m,6H),1.29(s,3H).

[0438] Example 43B was prepared using a similar synthetic route as in Example 42: LCMS(ESI):[M+H] + =664.2; 1H NMR(400MHz,CD3OD)δppm 7.74(dd,J=5.9,9.1Hz,1H),7.48(s,1H),7.35-7.23(m,2H),6.94(d,J=2. 6Hz,1H),5.41-5.19(m,1H),4.30-4.26(m,1H),4.25-4.16(m,2H),4.06(br d,J=13.4Hz,1H),3.89-3.80(m,1H),3.66-3.54(m,3H),3.46-3.40(m,1H),3.38-3.33(m,1H),3.29-2.96(m,6H),2.65(br d,J=3.0Hz,2H),2.39-2.10(m,4H),2.03-1.71(m,6H),1.27(s,3H).

[0439] Example 44: 1-(3,15-difluoro-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethyl-1-one

[0440]

[0441] Step 1: Add 4A molecular sieve (60.0 mg) and sodium tert-butoxide (55.0 mg, 0.55 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (60.0 mg, 0.09 mmol) and (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57.0 mg, 0.37 mmol) in tetrahydrofuran (800.0 μL). The solution was stirred at 60 °C for 16 hours. The reaction solution was diluted with water (1 mL), extracted with ethyl acetate (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid compound 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50.0 mg, 0.06 mmol, yield 66%). LCMS (ESI): [M+H + =814.4.

[0442] Step 2: At 0°C, acetyl chloride (2.60 μL, 0.04 mmol) and triethylamine (15.0 μL, 0.11 mmol) were added to a solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (30.0 mg, 0.04 mmol) in dichloromethane (400.0 μL). The solution was stirred at 20°C for 2 hours. The reaction mixture was diluted with water (1 mL), extracted with dichloromethane (1 mL * 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-80%) to give a yellow solid 1-(11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)yl)ethyl-1-one (25.0 mg, 0.03 mmol, yield 79%). LCMS (ESI): [M+H + =856.4.

[0443] Step 3: Add tetrabutylammonium fluoride (1M tetrahydrofuran solution, 187.0 μL, 0.18 mmol) to a solution of 1-(11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)yl)ethyl-1-one (20.0 mg, 0.02 mmol) in tetrahydrofuran (400.0 μL). Stir the solution at 20 °C for 2 hours. The reaction solution was diluted with water (1 mL), extracted with ethyl acetate (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid crude compound 1-(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethyl-1-one (20.0 mg, 0.03 mmol). LCMS (ESI): [M+H] + =742.3.

[0444] Step 4: Add hydrogen chloride (4M dioxane solution, 19 μL, 0.07 mmol) to a solution of 1-(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethyl-1-one (14 mg, 0.02 mmol) in acetonitrile (200.0 μL), and stir the reaction at 20 °C for 2 hours. Concentrate the solution, add dimethyl sulfoxide (1 mL), and adjust the pH to 8 with triethylamine. The mixture was purified by preparative HPLC to give compound 1-(3,15-difluoro-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)acet-1-one (1.05 mg, 1.47 μmol, yield 8%). LCMS (ESI): [M+H + =698.2; 1H NMR (400MHz, CD3OD) δppm 8.17-7.92(m,1H),7.74-7.62(m,1H),7.32-7.24(m,2H),7.24-6.84(m,1H),5.07(br d,J=7.09Hz,2H),4.52-4.33(m,3H),4.15(br d,J=12.96Hz,1H),4.00-3.58(m,2H),3.56-3.44(m,2H),2.99-2.73(m,4H),2 .62-2.32(m,2H),2.20(s,5H),2.12-1.51(m,8H),1.42-1.18(m,8H),0.92(br d, J = 17.36 Hz, 1H).

[0445] Example 45: 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0446]

[0447] Step 1: Under a nitrogen atmosphere and at 25°C, methanesulfonic anhydride (43 mg, 0.25 mmol) was added to a solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50 mg, 0.06 mmol) and pyridine (4 μL, 0.03 mmol) in dichloromethane (600 μL). The mixture was stirred at 20°C for 2 hours. Dilute with water (1 mL), extract with dichloromethane (1 mL x 3), dry the combined organic phases with sodium sulfate, filter, concentrate the filtrate to give a brown solid compound 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50 mg, 44.8 μmol, yield 73%). LCMS (ESI): [M+H+ =892.5.

[0448] Step 2: Under nitrogen atmosphere at 25°C, add tetrabutylammonium fluoride (1M tetrahydrofuran solution, 538 μL, 0.538 mmol) to a tetrahydrofuran (1 mL) solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (48 mg, 0.05 mmol). The reaction mixture is stirred at 25°C for 2 hours. Water (1 mL) was added to the solution, and the mixture was extracted with ethyl acetate (1 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown solid crude compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (37 mg, 47.6 μmol, yield 88%). LCMS (ESI): [M+H] + =778.4.

[0449] Step 3: Under a nitrogen atmosphere, at 25°C, pyridine hydrofluoric acid salt (500 μL, 0.01 mmol) was added to a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (36 mg, 0.05 mmol) in dichloromethane (500 μL). The reaction was stirred at 25°C for 16 hours. The reaction was quenched to neutral with triethylamine, filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(methanesulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (1.68 mg, 2.3 μmol, yield 5%). LCMS (ESI): [M+H]+ =734.4; 1 H NMR (400MHz, CD3OD) δppm 8.41 (s, 1H), 7.69 (dd, J=5.9, 8.9Hz, 1H), 7.42 (d, J=2.5Hz, 1H), 7.30-7.21 (m, 2H), 5.16 (br s,2H),4.53-4.45(m,2H),4.33-4.05(m,3H),3.76-3.64(m,2H),3.58-3.48(m,1H),3.45-3.36(m,2H),3.03(br s,1H),2.98-2.93(m,1H),2.90(s,3H),2.79(br d,J=14.1Hz,1H),2.71-2.61(m,1H),2.41-2.25(m,2H),2.19-2.00(m,4H),1.89-1.71(m,4H),1.45(br s,1H),1.38-1.28(m,4H),1.22-1.08(m,2H),1.06-0.90(m,2H).

[0450] Example 46: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteratedmethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0451]

[0452] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol) in N,N-dimethylformamide (1.00 mL), add deuterated iodomethane (16.6 μL, 0.26 mmol) and cesium carbonate (47.0 mg, 0.14 mmol). Stir the mixture at 25 °C for 4 hours. Dilute with water (1 mL), extract with ethyl acetate (1 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-(trideuteratedmethyl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol, 98% yield). LCMS (ESI): [M+H] + =780.3.

[0453] Step 2: Add sodium tert-butoxide (123 mg, 1.28 mmol) and 4A molecular sieve (50 mg) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-(trideuteratedmethyl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (40.8 mg, 0.27 mmol) in tetrahydrofuran (1.00 mL). The mixture was stirred at 60 °C for 16 hours. It was diluted with water (1 mL), extracted with ethyl acetate (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to give a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-(trideuteratedmethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.12 mmol, yield 93%). LCMS(ESI): [M+H] + =839.4.

[0454] Step 3: Add hydrogen chloride (4M dioxane solution, 1.79 mL, 7.15 mmol) to a solution of compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-(trideuteratedmethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.12 mmol) in acetonitrile (1.00 mL). Stir the solution at 25 °C for 16 hours. The reaction solution was concentrated under vacuum, and the residue was added to acetonitrile (1 mL) and neutralized with triethylamine (until pH > 7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteratedmethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (42.1 mg, 0.06 mmol, yield 52%). LCMS (ESI): [M+H] + =681.4. 1 H NMR (400MHz, CD3OD) δppm 7.87(d,J=9.5Hz,1H),7.70(dd,J=6.0,9.0Hz,1H),7.32-7.20(m,2H),6.89(d,J=2.6Hz,1H),5.36(br s,1H),4.33-4.23(m,2H),4.20(d,J=10.5Hz,1H),4.10(br t,J=14.6Hz,1H),3.66-3.52(m,2H),3.50-3.32(m,4H),3.29-3.13(m,3H),3.12-2.95(m,3H),2. 84-2.66(m,2H),2.39-2.09(m,4H),2.03-1.82(m,4H),1.81-1.70(m,2H),1.29(d,J=6.3Hz,3H).

[0455] Example 47: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0456]

[0457] Example 47: LCMS(ESI):[M+H) was prepared using a similar synthetic route as in Example 46. + =678.2. 1 H NMR(400MHz,CD3OD)δppm 7.90(s,1H),7.70(dd,J=6.1,8.9Hz,1H),7.30-7.21(m,2H),6.89(d,J= 2.6Hz,1H),5.39-5.20(m,1H),4.35-4.07(m,4H),3.64-3.54(m,2H),3. 47-3.33(m,4H),3.29-3.13(m,3H),3.12-2.94(m,3H),2.86-2.67(m,5H ),2.39-2.10(m,4H),2.03-1.94(m,2H),1.92-1.69(m,4H),1.30(s,3H).

[0458] Example 48: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0459]

[0460] Example 48: LCMS(ESI):[M+H) was prepared using a similar synthetic route as in Example 46. + =672.3. 1H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.92 (d, J = 13.33Hz, 1H), 7.73 (dd, J = 9.05, 6.11Hz, 1H), 7.36-7.21 (m, 2H), 6.91 (s, 1H), 5.17 (br s,2H),4.66-4.34(m,3H),4.27-4.05(m,2H),3.70-3.57(m,2H),3.55-3.36(m,6H),3.18-2.91(m,4H),2.77(br d,J=10.03Hz,5H),2.68(br d,J=15.41Hz,1H),2.33-2.01(m,5H),1.94-1.73(m,3H),1.32(d,J=6.85Hz,3H).

[0461] Example 49: 3,15-difluoro-13-(((2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0462]

[0463] Example 49: LCMS(ESI):[M+H) was prepared using a similar synthetic route as in Example 46. + =690.3. 1 H NMR (400MHz, CD3OD) δppm 8.47 (br s, 1H), 7.91 (br d, J=12.1Hz, 1H), 7.73 (dd, J=9.1, 6.2Hz, 1H), 7.34-7.22 (m, 2H), 6.90 (br s,1H),5.54-5.32(m,1H),5.08(br s,2H),4.49-4.30(m,3H),4.23-4.08(m,2H),4.02(br d,J=13.8Hz,1H),3.78(br d,J=13.7Hz,1H),3.68-3.58(m,3H),3.50-3.43(m,2H),3.18-2.95(m,3H),2.86(br s,1H),2.76(br d,J=11.7Hz,5H),2.62-2.11(m,5H),1.89-1.76(m,3H),1.31(d,J=6.7Hz,3H).

[0464] Example 50: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ylmethylcarbamate

[0465]

[0466] Step 1: At 25°C, triethylamine (14 μL, 0.10 mmol) and methylcarbamoyl chloride (2.20 mg, 0.02 mmol) were added to a solution of 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (13 mg, 0.02 mmol) in dichloromethane (1300 μL). The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with water (1 mL), extracted with dichloromethane (1 mL * 3), and the combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ylmethylcarbamate (3.43 mg, 4.76 μmol, yield 24%). LCMS (ESI): [M+H] + =721.3. 1H NMR (400MHz, CD3OD) δppm 7.94 (dd, J=6.1, 8.9Hz, 1H), 7.85-7.77 (m, 1H), 7.52 (s, 1H), 7.41 (br t,J=9.6Hz,1H),7.22-7.13(m,1H),5.41-5.20(m,1H),4.37-4.28(m,1H),4.26-4.17(m,2H),4.09(br d,J=13.3Hz,1H),3.87-3.73(m,1H),3.64-3.51(m,3H),3.47-3.35(m,4H),3.29-3.21(m,2H),3.14-3.01(m,2H),2.80(s,3H),2.67(br s,2H),2.43-1.71(m,10H),1.29(s,3H).

[0467] Example 51: 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yldecanoate

[0468]

[0469] Step 1: Add 4A molecular sieve (600.0 mg) and sodium tert-butoxide (401.0 mg, 4.09 mmol) to a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500.0 mg, 0.68 mmol) and (S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (209.0 mg, 1.36 mmol) in tetrahydrofuran (6.00 mL). The solution was stirred at 60 °C for 16 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (4 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of methanol / dichloromethane) to give a yellow solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (400.0 mg, 0.48 mmol, yield 70%). LCMS (ESI): [M+H] + =830.5.

[0470] Step 2: Add hydrogen chloride (4M dioxane solution, 4.06 mL, 16.2 mmol) to a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (150 mg, 0.18 mmol) in acetonitrile (2.00 mL), and stir the reaction at 20 °C for 16 hours. The solution was concentrated to give compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (150.0 mg, 0.22 mmol, yield 123%). LCMS (ESI): [M+H] + =672.3.

[0471] Step 3: At -40°C, add diisopropylethylamine (116.0 μL, 0.66 mmol) and n-decanoyl chloride (57.0 μL, 0.29 mmol) to a solution of 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (150 mg, 0.22 mmol) in dichloromethane (2.00 mL). Stir the solution at 20°C for 0.5 hours. The reaction mixture was added to water (3 mL), extracted with dichloromethane (1.5 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-80% gradient of ethyl acetate / petroleum ether) to give a yellow solid compound (30.0 mg, purity 85%). The obtained compound was purified by preparative HPLC to give a yellow solid 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yldecanoate (17.19 mg, 20.8 μmol, yield 9%). LCMS (ESI): [M+H] + =826.5. 1 H NMR (400MHz, CDCl3) δppm 7.78 (dd, J=8.6, 6.3Hz, 1H), 7.65 (t, J=2.6Hz, 1H), 7.59 (br d,J=16.5Hz,1H),7.34-7.29(m,1H),7.06(dd,J=6.0,2.5Hz,1H),4.95(br s,2H),4.35-4.14(m,4H),3.84-3.55(m,3H),3.50-3.21(m,6H),3.20-3.04(m,3H),2.94-2.73(m,6H),2.70-2.54(m,5H),2.41(br d,J=15.9Hz,1H),2.18(td,J=12.0,5.5Hz,1H),2.07-1.87(m,7H),1.80-1.71(m,5H),1.69-1.57(m,2H),1.44-1.33(m,7H),0.88(br t,J=6.7Hz,3H).

[0472] Example 52: (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0473]

[0474] Step 1: Add sodium tert-butoxide (39.2 mg, 0.41 mmol) to a solution of (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (20.0 mg, 0.03 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (10.8 mg, 0.07 mmol) in tetrahydrofuran (0.30 mL). Stir the mixture at 60 °C for 16 hours. Cool to room temperature and dilute with water (0.5 mL). Extract with ethyl acetate (0.5 mL * 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Purify the residue by preparative HPLC to give two stereoisomers of compound (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol. Isomer 1, Example 05-546A-100: Shorter retention peak on HPLC, yellow solid (1.99 mg, 3.07 μmol, yield 9%). LCMS(ESI):[M+H] + =648.2.

[0475] Example 52A: LCMS(ESI): [M+H] + =648.3. 1H NMR(400MHz,CD3OD)δppm 8.09(d,J=7.2Hz,1H),8.01(dd,J=9.0,6.1Hz,1H),7.63-7.51(m,2H),7.46-7.31(m,2H),5.48-5.28(m,1H),4.45-4 .21(m,3H),4.17-4.07(m,1H),3.91-3.79(m,1H),3.68-3.34(m,8H),3.29-3.32(m,1H),3.20-3.03(m,2H),2.71(br s,2H),2.50-2.05(m,6H),2.02-1.71(m,4H),1.32-1.25(m,3H).

[0476] Example 52B: LCMS(ESI): [M+H] + =648.3. 1 H NMR(400MHz,CD3OD)δppm 8.09(d,J=7.3Hz,1H),8.01(dd,J=9.0,6.2Hz,1H),7.64-7.52(m,2H),7.47-7.33(m,2H),5.44-5.24(m,1H),4.38-4.18(m,3H),4.12(br d,J=13.1Hz,1H),3.85(dt,J=12.6,6.3Hz,1H),3.66-3.34(m,8H),3.29-3.22(m,1H),3.15-3.01(m,2H),2.71(br d,J=3.9Hz,2H),2.44-1.69(m,10H),1.40-1.25(m,3H).

[0477] Example 53: (R)-1-(3,15-difluoro-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0478]

[0479] Example 53 was prepared using a similar synthetic route as in Example 52: LCMS(ESI):[M+H] + =642.3. 1H NMR (400MHz, CD3OD) δppm 8.02(m,2H),7.84-7.69(m,1H),7.61-7.55(m,1H),7.44-7.34(m,2H),5.10(br s,2H),4.48-4.06(m,3H),4.03-3.71(m,2H),3.69-3.37(m,6H),3.32-3.03(m,3H), 2.98-2.85(m,1H),2.81-2.47(m,3H),2.35-1.63(m,10H),1.30(brd,J=8.7Hz,3H).

[0480] Example 54: (R)-1-(3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0481]

[0482] Example 54: LCMS (ESI): [M+H) was prepared using a similar synthetic route as in Example 52. + =656.3. 1 H NMR (400MHz, CD3OD) δppm 8.08-7.83(m,3H),7.50(br t,J=7.7Hz,1H),7.37(brt,J=9.6Hz,1H),7.29(br d,J=6.9Hz,1H),5.06(br s,2H),4.48-4.24(m,3H),4.20-4.10(m,1H),3.91(br d,J=12.8Hz,1H),3.72-3.35(m,7H),3.09-2.98(m,2H),2.92-2.77(m,3H),2.74-2.66(m,3H),2.65-2.51(m,1H),2.33-1.54(m,10H),1.30(br d, J = 6.5 Hz, 3H).

[0483] Example 55: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0484]

[0485] Step 1: Add triethylamine (1.03 mL, 7.40 mmol) to a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (3.9 g, 6.17 mmol), 4-methylbenzenesulfonyl azide (1.95 g, 7.40 mmol), and cuprous iodide (0.12 g, 0.62 mmol) in chloroform (50 mL) and water (0.28 mL, 15.41 mmol). The mixture was stirred for 12 hours under nitrogen protection and at 20°C. It was then diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-p-methylbenzenesulfonylacetamide (5.0 g), which was a brown solid. LCMS (ESI): [M+H] + =820.0.

[0486] Step 2: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-p-methylbenzenesulfonylacetamide (5.4 g, 6.59 mmol) in N,N-dimethylformamide (50 mL), iodomethane (1.23 mL, 19.76 mmol) and potassium carbonate (2.73 g, 19.76 mmol) were added. The mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthyl-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (2.38 g, 2.85 mmol, yield 43%). LCMS (ESI): [M+H] + =834.2.

[0487] Step 3: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphth-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (11.5 g, 13.79 mmol) and triethylamine (9.59 mL, 68.96 mmol) in dichloromethane (140 mL), tert-butyldimethylsilyltrifluoromethanesulfonate (5.20 mL, 41.38 mmol) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 16 hours. It was diluted with water (40 mL), extracted with dichloromethane (40 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give a brown solid compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (12.7 g, 13.41 mmol, yield 97%). LCMS (ESI): [M+H] + =948.4.

[0488] Step 4: At -70°C, add 1M diisobutylaluminum hydride (42.19 mL, 42.19 mmol) to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)-N-methyl-N-p-methylbenzenesulfonylacetamide (12.50 g, 13.19 mmol) in 155 mL of dichloromethane. Stir the mixture at -70°C for 1 hour, quench with acetic acid (7.25 mL, 126.58 mmol), dilute with water (100 mL), stir, and let stand for 16 hours. Extraction was then performed using dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether:dichloromethane = 3:1)) to give compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)acetaldehyde (7.70 g, 10.08 mmol, yield 76%), as a brown solid. LCMS (ESI): [M+H] + =765.3.

[0489] Step 5: At 0°C, borane / tetrahydrofuran (1M, 41mL, 40.71mmol) was added to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)acetaldehyde (18.50g, 24.19mmol) in 190mL of tetrahydrofuran. The reaction mixture was stirred at 10°C for 16 hours. The reaction mixture was quenched with methanol at 0°C. The mixture was concentrated under reduced pressure to give a brown solid compound, 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethanol (18.50 g, 21.71 mmol, 90% yield). LCMS (ESI): [M+H] + =767.8.

[0490] Step 6: Under nitrogen protection, ethyl 2-diazopropionate (752 mg, 5.87 mmol) was added dropwise to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethanol-1-ol (1.00 g, 1.30 mmol) and rhodium acetate dimer (28.8 mg, 0.07 mmol) in dichloromethane (10.0 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was quenched with methanol (5 mL) and evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give a yellow oily crude compound ethyl 2-(2-(8-(4-(((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethoxy)propionate (800 mg, 0.92 mmol, yield 71%). LCMS (ESI): [M+H] + =867.3.

[0491] Step 7: Add 300 mg of dry palladium on carbon to a solution of ethyl 2-(2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethoxy)propionate (1.34 g, 1.55 mmol) in 60 mL of ethyl acetate. The mixture was stirred for 16 hours under a hydrogen atmosphere (45 psi) and at 20°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily compound, ethyl 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethoxy)propionate (1.28 g, 1.53 mmol, yield 99%). LCMS (ESI): [M+H] + =837.3.

[0492] Step 8: Add lithium hydroxide (385 mg, 9.18 mmol) to a solution of ethyl 2-(2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthyl-1-yl)ethoxy)propionate (1.28 g, 1.53 mmol) in tetrahydrofuran (25.0 mL) and water (2.5 mL). Stir the mixture at 60 °C for 5 hours and adjust the pH to 5-6 using 1 M hydrochloric acid solution. Extracted with ethyl acetate (10 mL * 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a yellow solid compound 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethoxy)propionic acid (1.23 g, 1.52 mmol, yield 99%). LCMS (ESI): [M + H + =809.3.

[0493] Step 9: Add n-butylphosphonic anhydride (50% ethyl acetate solution, 3.29 g, 4.56 mmol) to a solution of 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethoxy)propionic acid (1.23 g, 1.52 mmol) and diisopropylethylamine (10.6 mL, 60.82 mmol) in dioxane (49.0 mL). Stir the reaction mixture at 60 °C for 16 hours. Cool to room temperature, add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL * 3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to give a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (1.2 g, 1.52 mmol, 100% yield). LCMS(ESI):[M+H] + =791.3.

[0494] Step 10: Compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (1.2 g, 1.52 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (102 mg, 0.15 mmol) were dissolved in tetrahydrofuran (84 mL), and benzylsilane (3.74 mL, 30.35 mmol) was added under nitrogen atmosphere and stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, 0-30% gradient tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give a yellow solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (520 mg, 0.67 mmol, yield 44%). LCMS (ESI): [M+H] + =777.3.

[0495] Step 11: Add sodium tert-butoxide (569 mg, 5.92 mmol) to a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol), 4A molecular sieve, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (160 mg, 1.01 mmol) in tetrahydrofuran (5.00 mL). Stir the mixture at 60 °C for 16 hours. Cool to room temperature, dilute with water (3 mL), extract with ethyl acetate (3 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient methanol / dichloromethane) to give a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (380 mg, 0.59 mmol, yield 77%). LCMS(ESI):[M+H] + =836.7.

[0496] Step 12: Add hydrogen chloride (2M dioxane solution, 27.3 mL, 54.54 mmol) to a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (380 mg, 0.45 mmol) in acetonitrile (3.00 mL). Stir the solution at 25 °C for 16 hours. The reaction solution was concentrated under vacuum, and the residue was added to acetonitrile (1 mL) and neutralized with triethylamine (until pH > 7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (60.0 mg, 0.09 mmol, yield 19%). LCMS (ESI): [M+H] + =678.2. 1 H NMR(400MHz,CD3OD)δppm 7.76(dd,J=6.2,8.7Hz,1H),7.59-7.39(m,1H),7.36-7.22(m,2H),7.05-6. 90(m,1H),5.42-5.24(m,1H),4.43-3.99(m,4H),3.92-3.80(m,1H),3.73(br s,1H),3.64-3.34(m,3H),3.31-3.23(m,3H),3.09-3.03(m,1H),2.93-2.52(m,4H),2. 43-2.10(m,4H),2.07-1.84(m,4H),1.83-1.70(m,2H),1.31(s,3H),1.10-0.91(m,3H).

[0497] Example 56: (R)-1-(17-amino-3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0498]

[0499] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL), iodomethane (81.0 μL, 1.32 mmol) and cesium carbonate (235 mg, 0.72 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (3 mL), extracted with ethyl acetate (5 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (petroleum ether / dichloromethane, v / v)) to give a yellow solid (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol, 90% yield). LCMS (ESI): [M+H] + =777.3.

[0500] Step 2: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol) in acetonitrile (8.00 mL), hydrogen chloride (4 M dioxane solution, 1.04 mL, 4.14 mmol) was added. The mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure to give a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (430 mg, 0.59 mmol, 99% yield). LCMS (ESI): [M+H] + =733.2.

[0501] Step 3: Diisopropylethylamine (98 μL, 0.55 mmol) was added to a solution of compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (135 mg, 0.18 mmol) in dichloromethane (1.35 mL). Trifluoromethanesulfonic anhydride (46.5 μL, 0.28 mmol) was slowly added dropwise at -78 °C, and the solution was stirred at -70 °C for 4 hours. After the reaction was complete, the mixture was quenched with water (1 mL), extracted with dichloromethane (1 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow solid crude compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yltrifluoromethanesulfonate (195 mg). LCMS(ESI):[M+H] + =865.2.

[0502] Step 4: In a nitrogen atmosphere, to (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yltrifluoromethanesulfonate To a solution of 180 mg (0.21 mmol) of tetrahydrofuran (1.80 mL), tert-butyl carbamate (34.1 mg, 0.29 mmol), cesium carbonate (203 mg, 0.62 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (12.0 mg, 0.02 mmol), and tris(dibenzylacetone)dipalladium (19.1 mg, 0.02 mmol) were added. The mixture was stirred at 70 °C for 2 hours. After cooling naturally to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (petroleum ether / dichloromethane, v / v)) to give the green solid compound tert-butyl(R)-(11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (144 mg, 0.17 mmol, yield 83%). LCMS (ESI): [M+H + =832.4.

[0503] Step 5: Add 4A molecular sieve (50 mg) and sodium tert-butoxide (66.1 mg, 0.67 mmol) to a solution of tert-butyl(R)-(11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (70.0 mg, 0.08 mmol) and (S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (21.9 mg, 0.14 mmol) in tetrahydrofuran (1.00 mL). Stir the mixture at 60 °C for 16 hours. The mixture was allowed to cool naturally to room temperature, diluted with water (1 mL), and extracted with ethyl acetate (1 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to give a brown solid compound tert-butyl(11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (20.0 mg, 0.02 mmol, yield 27%). LCMS(ESI):[M+H] + =885.5.

[0504] Step 6: Add hydrogen chloride (4M dioxane solution, 339 μL, 1.36 mmol) to a solution of tert-butyl(11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (20.0 mg, 0.02 mmol) in dichloromethane (200 μL). Stir the solution at 25 °C for 16 hours. The reaction solution was concentrated under vacuum, and the residue was added to dichloromethane (1 mL) and neutralized with triethylamine (until pH > 7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound (R)-1-(17-amino-3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (formate, 7.58 mg, 11.30 μmol, yield 50%). LCMS (ESI): [M+H] + =671.2. 1H NMR (400MHz, CD3OD) δppm 8.54 (s, 1H), 7.85 (d, J = 9.2Hz, 1H), 7.62 (dd, J = 6.1, 9.0Hz, 1H), 7.35-7.08 (m, 2H), 6.84 (d, J = 2.3Hz, 1H), 5.11 (br s,2H),4.61-4.26(m,3H),4.15(br t,J=14.1Hz,1H),4.00(br d,J=13.6Hz,1H),3.72-3.47(m,4H),3.46-3.35(m,4H),3.18-3.07(m,1H),3.05-2.85(m,3 H),2.84-2.66(m,5H),2.61(brd,J=16.3Hz,1H),2.28-1.72(m,8H),1.30(d,J=5.1Hz,3H).

[0505] Example 57: 13-((2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0506]

[0507] Example 57: LCMS (ESI): [M+H) was prepared using a similar synthetic route as in Example 16. + =692.7. 1 H NMR (400MHz, CD3OD) δppm 7.61-7.53(m,1H),7.28-7.07(m,3H),6.83(d,J=2.6Hz,1H),4.92(br d,J=3.8Hz,2H),4.23-4.06(m,3H),3.97(br d,J=13.1Hz,1H),3.65(br t,J=14.6Hz,2H),3.41-3.32(m,2H),3.30-3.24(m,1H),3.10-2.98(m,1H),2.93-2.81(m,1H),2.75-2.67(m,1H),2.60-2.46( m,3H),2.31(q,J=14.4Hz,2H),2.14-2.00(m,1H),1.80-1.60(m,4H),1.55-1.38(m,2H),1.35-1.16(m,6H),0.95-0.84(m,1H).

[0508] Example 1: AlphaLISA compound screening experiment

[0509] Experimental methods:

[0510] 1. Prepare the test buffer:

[0511] Buffer 1 composition and final concentration: 25mM HEPES pH7.5, 10mM MgCl2, 0.01% Triton X-100.

[0512] Buffer 2 composition and final concentration: 25mM HEPES pH7.5, 10mM MgCl2, 0.01% Triton X-100, 1mM DTT.

[0513] 2. Experimental design and compound preparation:

[0514] 1> Prepare compounds using ECHO555 automated plate-making instrument. Test concentration: The highest detectable concentration of the compound is 10 μM or 1 μM, 3-fold dilution, 10 concentrations, 2 replicates for each concentration, 0.5% DMSO.

[0515] 2> High control: 30 replicates, 0.5% DMSO, KRAS protein involved in the reaction, as 0% inhibition.

[0516] 3> Low signal control: 30 replicates, 0.5% DMSO, no KRAS protein involved in the reaction, as 100% inhibition.

[0517] 3. Experimental steps:

[0518] a. KRAS-GDP protein experimental procedures

[0519] 1> Add 5 μl of KRAS solution prepared with buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group. The final concentration of KRAS reaction is 5 nM (initially 40 nM, optimized to 5 nM). Incubate at room temperature for 1 h.

[0520] 2> Add 5 μl of SOS1 and GTP mixed solution prepared with buffer 2 to each well of the test plate. The final reaction concentrations are 50 nM and 125 μM (initially 250 nM and 625 μM), respectively. Incubate at room temperature for 1 h.

[0521] 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptorbeads mixed solution prepared with buffer 2 to each well of the test plate. The final reaction concentrations are 50 nM and 20 μg / ml, respectively. Incubate at room temperature for 1 h.

[0522] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final concentration of the reaction is 20 μg / ml. Incubate at room temperature for 1 h.

[0523] 5> Use an EnVision microplate reader to read the signal value of the test plate. The excitation wavelength is 680nm and the emission wavelength is 615nm.

[0524] b. KRAS-GTP protein experimental procedures

[0525] 1> Mix the prepared protein solution with the SOS1-GTP mixed solution (concentration consistent with GDP protein) at a volume ratio of 1:1, and pre-incubate at room temperature for 1 hour.

[0526] 2> Add 10 μl of the mixture from step 1 to each well of the high signal control group and compound test wells on the test plate; add 5 μl of buffer 1 and 5 μl of SOS1 and GTP mixture to each well of the low signal control group, and incubate at room temperature for 1 h.

[0527] 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptorbeads mixed solution prepared with buffer 2 to each well of the test plate. The final reaction concentrations are 50 nM and 20 μg / ml, respectively. Incubate at room temperature for 1 h.

[0528] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final concentration of the reaction is 20 μg / ml. Incubate at room temperature for 1 h.

[0529] 5> Use an EnVision microplate reader to read the signal value of the test plate. The excitation wavelength is 680nm and the emission wavelength is 615nm.

[0530] c. KRAS-GCP protein experimental procedures

[0531] 1> Add 5 μl of KRAS solution prepared with buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group. The final concentration of KRAS reaction is 5 nM. Incubate at room temperature for 1 h.

[0532] 2> Add 5 μl of buffer 2 to each well of the test plate and incubate at room temperature for 1 h.

[0533] 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptorbeads mixed solution prepared with buffer 2 to each well of the test plate. The final reaction concentrations are 50 nM and 20 μg / ml, respectively. Incubate at room temperature for 1 h.

[0534] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final concentration of the reaction is 20 μg / ml. Incubate at room temperature for 1 h.

[0535] 5> Use an EnVision microplate reader to read the signal value of the test plate. The excitation wavelength is 680nm and the emission wavelength is 615nm.

[0536] 4. Experimental Data Analysis:

[0537] 1> Calculate the high control average and low control average based on the raw data.

[0538] 2> Calculate the inhibition rate of the compound sample signal using the following formula:

[0539] (High control average-Sample signal / High control average-Low control average)*100%

[0540] 3. Using the four-parameter fitting mode (log(inhibitor) vs. response - Variable slope (four parameters)) in Graphpad Prism software, concentration response curves were fitted to the compounds and their inhibition rates at different concentrations to the experimental signal, and the IC50 of the compounds was calculated. 50 value.

[0541] Experimental materials:

[0542]

[0543] Experimental apparatus:

[0544]

[0545] Experimental results:

[0546] The inhibitory effects of the compounds of this invention on the GDP, GTP, and GCP proteins of KRAS G12D are shown in Table 1.

[0547]

[0548] Example 2: ERK phosphorylation cell experiment

[0549] AGS_ERK protein phosphorylation detection

[0550] Day 1: AGS cells were seeded into 384-well cell culture plates and cultured overnight at 37°C in a 5% CO2 cell culture incubator.

[0551] Day 2: The compound was added to the plate using an Echo550, and the cells were cultured at 37°C in a 5% CO2 incubator for 3 hours. Finally, the cell culture plates were fixed with paraformaldehyde, permeated with methanol, and blocked with blocking solution. Then, a primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) was added, and the plates were incubated overnight at 4°C.

[0552] Day 3: Discard the primary antibody and add the secondary antibody mixture (Goat anti-rabbit 800CW, Goat anti-mouse 680RD), incubate at room temperature in the dark. Finally, wash three times with PBST, invert the cell culture plate and centrifuge for 1 minute. Read the fluorescence signal value using an Odyssey CLx.

[0553] ERK phosphorylation is calculated using the following formula:

[0554] Relative expression level: (Ratio of fluorescence signal of compound – average of positive control) / (average of negative control – average of positive control)

[0555] Negative control: DMSO

[0556] Positive control: 10 μM Reference

[0557] XLFit 5.0 calculates IC by fitting the parameter formula. 50 value:

[0558] Y=Bottom+(Top–Bottom) / (1+10^((Log IC 50 –X)×HillSlope))

[0559] X: Log value of compound concentration

[0560] Y: Average relative expression level of p-ERK between replicates

[0561] The inhibitory effects of the compounds of this invention on pERK in AGS and AsPC-1 cells are shown in Table 2.

[0562]

[0563]

[0564] NT: Not tested

[0565] Example 3: 3D cell proliferation experiment

[0566] 3D proliferation experiment of AGS and AsPC-1 cells

[0567] The diluted analyte compound was added to 384-well low-adsorption cell culture plates using a nanoliter pipetting system (LABCYTE, P-0200). After cell seeding, the plates were placed in a 37°C, 5% CO2 incubator. After co-incubating the compound with the cells for 5 days, the following steps were taken: The 3D reagent was used, and the luminescence value was read using an Envision multi-functional microplate reader (the light signal is directly proportional to the amount of ATP in the system, and the ATP content directly represents the number of viable cells in the system). Finally, the IC50 of the compound was obtained using a non-linear fitting formula with XLFIT software. 50 (Half-maximal inhibitory concentration).

[0568] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0569] X: Log value of compound concentration

[0570] Y: Inhibition rate (%)

[0571] Inhibition rate (%) = 100 × (Negative control average value - Compound reading) / (Negative control average value - Positive control average value)

[0572] Negative control: DMSO

[0573] Positive control: Medium only

[0574] The inhibitory effects of the compounds of this invention on the 3D proliferation of AGS and AsPC-1 cells are shown in Table 3.

[0575]

[0576]

Claims

1. A heterocyclic compound as shown in Formula I-1, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative: in, In Formula I-1, Cy1 represents a 6-membered aryl or a 6-membered heteroaryl; wherein, Cy1 may also be arbitrarily replaced by 0-3 elements selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced; In Formula I-1, Cy2 represents a 6-membered aryl or a 6-membered heteroaryl; wherein Cy2 may also be arbitrarily replaced by 0-3 elements selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halogenated (C1-C6), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced; Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;X 3 For N or CR X3 ; Among them, R X1 R X2 R X3 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ; Wherein, L1 and L2 independently represent the absence of, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-, and -NR. a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-(C1-C6 alkylene)C(O),-NR a C(O)(C1-C6 alkylene)-、-(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S. Among them, R 1 R 2 Each independently represents a 5-16 member saturated or unsaturated cycloalkyl group or a 5-16 member saturated or unsaturated heterocycloalkyl group, and the R... 1 R 2 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced; Among them, Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a -replaced; Or, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings; Among them, R a R b Each can independently represent hydrogen, C1-C6 alkyl, halogenated (C1-C6 alkyl), or C3-C6 cycloalkyl; or R a R b Together with the atoms they are attached to, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

2. A heterocyclic compound as shown in Formula I-1', its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative: in, In equation I-1', M 1 Indicates CR M1 Or N; M 2 Indicates CR M2 Or N; M 3 Indicates CR M3 Or N; M 4 Indicates CR M4 Or N; M 5 Indicates CR M5 Or N; M 6 Indicates CR M6 Or N; Among them, R M1 R M2 R M3 R M4 R M5 R M6 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced; Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;X 3 For N or CR X3 ; Among them, R X1 R X2 R X3 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ; Wherein, L1 and L2 independently represent the absence of, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-, and -NR. a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-(C1-C6 alkylene)C(O),-NR a C(O)(C1-C6 alkylene)-、-(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S. Among them, R 1 R 2 Each independently represents a 5-16 member saturated or unsaturated cycloalkyl group or a 5-16 member saturated or unsaturated heterocycloalkyl group, and the R... 1 R 2 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced; Among them, Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a -replaced; Or, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings; Among them, R a R b Each can independently represent hydrogen, C1-C6 alkyl, halogenated (C1-C6 alkyl), or C3-C6 cycloalkyl; or R a R b Together with the atoms they are attached to, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

3. The heterocyclic compound of formula I-1' according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, X 2 It represents CH or N.

4. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, X 3 Indicates CR X3 Or N, where R X3 Indicates H, halogen, OR a CN, NO2, SF5, POMe2, NH2, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl).

5. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, L1 indicates absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-、-NR a -(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-、-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocyclic alkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached thereto, they form a 3-6 saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, N, and S.

6. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, L1 represents O-C1-C6 alkylene-.

7. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, L1 represents -O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein, R T R T′ Together with the carbon atoms attached to them, they form 3-6 saturated or unsaturated rings.

8. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 1 The R indicates a 5-16 member saturated or unsaturated heterocyclic alkyl group. 1 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

9. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 1 It has any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Furthermore, the R mentioned 1 It can also be arbitrarily selected from 0-4 alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, 3-6 heterocyclic alkyl, 3-6 heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

10. The heterocyclic compound of formula I-1' according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 1 express: ； Among them, R 1' R 2' R 3' R 4' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ; Or R 1' With R 2' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 1' With R 2' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 3' With R 4' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 3' With R 4' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 5' With R 6' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 5' With R 6' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 7' With R 8' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 7' With R 8' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 9' With R 10' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 9' With R 10' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 11' With R 12' Together with the carbon atom it is bonded to, they form a double bond (C=) or C=O; or R 11' With R 12' Together with the atoms bonded to it, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be separated by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 2' With R 3' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 4' R 5' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 8' R 9' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 10' R 11' Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the rings may also arbitrarily be replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O.

11. The heterocyclic compound of formula I-1' according to claim 10, its pharmaceutically acceptable salt, its stereoisomer, wherein, R 1' R 2' R 3' R 4' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' Each can be independently represented as hydrogen, halogen, hydroxyl, carbonyl, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C2-C6 alkenyl, or C2-C6 alkynyl.

12. The heterocyclic compound of formula I-1' according to claim 10 or 11, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, The R mentioned 1 It has the following structure: or Among them, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' It has the definition of claim 10 or claim 11.

13. The heterocyclic compound of formula I-1' according to claim 10 or 11, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, The R mentioned 1 It has the following structure: Wherein, ring A is a 3-6 membered ring, and ring A may be arbitrarily replaced by 0-2 elements selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced; Among them, R 1' R 4' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' It has the definition of claim 10 or claim 11.

14. The heterocyclic compound of formula I-1' according to claim 10 or 11, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, The R mentioned 1 It has the following structure: Among them, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' It has the meaning as defined in claim 10 or claim 11, wherein R L R L’ Each can be used independently to represent hydrogen, C1-C6 alkyl, or halogen.

15. The heterocyclic compound of formula I-1' according to claim 10 or 11, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 1' R 2' R 5' R 6' R 7' R 8' R 9' R 10' R 11' R 12' Each of these can be independently represented as hydrogen, halogen, hydroxyl, C1-C6 alkyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), or hydroxyl (C1-C6 alkyl); R 3' R 4' Together with the atoms respectively bonded thereto, they form a 3-6 membered ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; wherein the ring is arbitrarily selected from 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a Substituents: 。 16. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, wherein, L2 indicates absence, -O-C1-C6 alkylene-, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -NR a -C1-C6 alkylene-, -C1-C6 alkylene-NR a - 17. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, L2 indicates that it does not exist.

18. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 2 It is any one of the following ring structures: (i), (ii), or (iii) Among them, W 1 Represents -(CR) W1 R W2 ) p -、-(CR W1 R W2 ) p -O-、-O-(CR W1 R W2 ) p -、-NR a -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -NR a -, -CH=CH- or NR W1 ; Among them, R W1 R W2 Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b Or R W1 R W2 Together with the carbon atom attached thereto, they form a 3-8 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; and the ring may also arbitrarily be separated by 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Among them, R 1" R 2" R 3" R 4" R 5" R 6" R 7" R 8" Each of these can be independently represented as hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(O)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b ; Or R 1" With R 2" Together with the atoms bonded to it, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 3" With R 4" Together with the atoms bonded to it, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 5" With R 6" Together with the atoms bonded to it, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 7" With R 8" Together with the atoms bonded to it, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 2" With R 3" Together with the atoms respectively attached to form substituted or unsubstituted 3-10 member saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 4" With R 5" Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 6" With R 7" Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O; Or R 5" With R W1 Together with the atoms respectively bonded thereto, they form substituted or unsubstituted 3- to 10-membered saturated or unsaturated rings, and the rings may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the arbitrary presence of 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, -OR a -SO3R a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R a The substituents are replaced by the substituents; or any CH2 in the ring is replaced by C=O.

19. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 2 It can be any of the following ring structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ; Wherein, the R 2 It can be arbitrarily composed of 0-4 ions selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(0)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

20. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, R 2 It can be any of the following ring structures: 、 、 、 、 、 、 、 、 、 ； Wherein, the R 2 It can be arbitrarily composed of 0-4 ions selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, halogen, halogenated (C1-C6 alkyl), halogenated (C1-C6 alkoxy), hydroxyl (C1-C6 alkyl), -OR a -C(0)R a -OC(O)R a -C(O)OR a -NO2, -SF5, -SO3R a -S(O)2R a , cyano, -C(O)NR a R b -NR a C(O)R a -NR a R b The substituents are replaced by the substituents.

21. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, wherein, R 2 It can be any of the following ring structures: 、 、 、 、 、 、 、 、 、 、 。 22. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, M 1 To M 6 It represents CH or N.

23. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, M 1 To M 6 It represents CH.

24. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, Y 1 Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenyl groups, and wherein any CR a R b It can be substituted by O, NH, -C(O), -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -P(O)R a - Replaced.

25. The heterocyclic compound of formula I-1' according to claim 24, its pharmaceutically acceptable salt, its stereoisomer, wherein, Y 1 Y 2 Together they form -(C1-C 10 (alkylene)-NR a -、-O-(C1- C 10 (alkylene)-NR a -、-NR a (C1-C 10 (alkylene)-O-, -(C1-C 10 (alkylene)-O-, -(C1-C 10 alkylene)-C(O)NR a -、-(C1- C 10 (alkylene)-NR a C(O)-、-(C1- C 10 alkylene)-O-(C1-C 10 (alkylene)-O-, -(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 (alkylene)-NR a -(C1- C 10 alkylene)-, -(C1-C 10 (alkylene)-NR a -(C1- C 10 alkylene)-O-, -(C1-C 10 (alkylene)-O-(C1-C) 10 (alkylene)-NR a -、- NR a - (C1- C 10 alkylene)-, -O-(C1-C 10 alkylene)-、-C(O)NR a -(C1- C 10 Alkylene)-, -NR a C(O) -(C1- C 10 alkylene)-, -(C1-C 10 (alkylene)-O-(C1-C) 10 alkylene)-, -O-(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 (alkylene)-O-(C1-C) 10 alkylene)-C(O), -(C1-C 10 alkylene)-C(O)-, -O-(C1-C 10 alkylene)-C(O)-, -C(O)-(C1-C 10 alkylene)-、-C(O)-(C1-C 10 alkylene)-O-, -O-(C1-C 10 alkylene)-C(O)NR a -、-C(O)NR a -(C1- C 10 (alkylene)-O-, -(C1-C 10 alkylene)-S-, -S-(C1-C 10 Alkylene)-.

26. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, Y 1 Y 2 Together they form 5-10 saturated or unsaturated rings, 6-10 aromatic rings, or 5-10 heteroaromatic rings.

27. The heterocyclic compound of formula I-1' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, and its deuterated derivative, wherein, Y 1 Y 2 Together they form any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 。 28. A compound, a pharmaceutically acceptable salt, its stereoisomers, and deuterated derivatives, having the following structures: 。

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